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The FASEB Journal. 2024;38:e70075.
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1 of 28
https://doi.org/10.1096/fj.202401409R
wileyonlinelibrary.com/journal/fsb2
Received: 20 June 2024
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Revised: 20 August 2024
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Accepted: 13 September 2024
DOI: 10.1096/fj.202401409R
REVIEW ARTICLE
Advances in natural products modulating autophagy
influenced by cellular stress conditions and their
anticancer roles in the treatment of ovarian cancer
DongxiaoLi
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DanboGeng
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MinWang
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any
medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
© 2024 The Author(s). The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.
Dongxiao Li and Danbo Geng contributed equally to this work and should be considered co- first author.
Abbreviations: AKT, protein kinase B; AMBRA1, activating molecule in Beclin- 1- regulated autophagy protein 1; AMPK, AMP- activated protein
kinase; ASK1, apoptosis signal- regulating kinase 1; ATF4, activating transcription factor 4; ATF6α, activating transcription factor 6 alpha; ATG,
autophagy- related gene; ATG5, autophagy related 5; ATG7, autophagy related 7; BRAF, B- rapidly accelerated fibrosarcoma; CAF, cancer- associated
fibroblast; CHOP, C/EBP homologous protein; CMA, chaperone- mediated autophagy; eIF2α, eukaryotic initiation factor 2 alpha; EMT, epithelial-
mesenchymal transition; EOC, epithelial ovarian cancer; ERAD, endoplasmic reticulum- associated degradation; ERK, extracellular signal- regulated
kinase; ERS, endoplasmic reticulum stress; FOXO1, Forkhead box O1; GCN2, general control nonderepressible 2; GRP78, glucose- regulated protein
78; HERPUD1, homocysteine- induced endoplasmic reticulum protein (Herp) ubiquitin- like domain member 1; HGSOC, high- grade serous ovarian
carcinoma; HRI, heme- regulated inhibitor; HSPA5, heat shock protein family A (Hsp70) member 5; IL- 6, interleukin 6; IRE1α, inositol- requiring
enzyme 1 alpha; ISR, integrated stress response; JNK, c- Jun N- terminal kinase; LC3, microtubule- associated protein 1 light chain 3 (also known as
MAP1LC3B); MAP1LC3, microtubule- associated protein 1 light chain 3; MAPK, mitogen- activated protein kinase; MEK, MAPK/ERK kinase; mTOR,
mechanistic target of rapamycin; mTORC1, mechanistic target of rapamycin complex 1; NRAS, neuroblastoma RAS viral oncogene homolog; OC,
ovarian cancer; OCs, ovarian cancers; p53, tumor protein p53; PARP, poly ADP- ribose polymerase; PERK, protein kinase R- like endoplasmic
reticulum kinase; PI3K, phosphatidylinositol 3- kinase; PIP3, phosphatidylinositol- 3,4,5- trisphosphate; PKR, protein kinase R; PTEN, phosphatase
and tensin homolog; Rheb, Ras homolog enriched in brain; ROS, reactive oxygen species; TRAF2, TNF receptor associated factor 2; ULK1, Unc- 51-
like kinase 1 (also known as ATG1); UPR, unfolded protein response; VPS, vacuolar protein sorting.
Department of Obstetrics and
Gynecology, Shengjing Hospital of
China Medical University, Shenyang,
China
Correspondence
Min Wang, Department of Obstetrics
and Gynecology, Shengjing Hospital of
China Medical University, Shenyang
110004, China.
Email: wangm@sj-hospital.org
Funding information
MOST | National Key Research and
Development Program of China
(NKPs), Grant/Award Number:
2018YFC1004203
Abstract
Autophagy is a conservative catabolic process that typically serves a cell- protective
function. Under stress conditions, when the cellular environment becomes unsta-
ble, autophagy is activated as an adaptive response for self- protection. Autophagy
delivers damaged cellular components to lysosomes for degradation and recy-
cling, thereby providing essential nutrients for cell survival. However, this func-
tion of promoting cell survival under stress conditions often leads to malignant
progression and chemotherapy resistance in cancer. Consequently, autophagy is
considered a potential target for cancer therapy. Herein, we aim to review how
natural products act as key modulators of autophagy by regulating cellular stress
conditions. We revisit various stressors, including starvation, hypoxia, endoplas-
mic reticulum stress, and oxidative stress, and their regulatory relationship with
autophagy, focusing on recent advances in ovarian cancer research. Additionally,
we explore how polyphenolic compounds, flavonoids, alkaloids, terpenoids,
and other natural products modulate autophagy mediated by stress responses,
affecting the malignant biological behavior of cancer. Furthermore, we discuss
their roles in ovarian cancer therapy. This review emphasizes the importance of
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1
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INTRODUCTION
Ovarian cancer ranks as the seventh most common
cancer and is the second leading cause of gynecologic
cancer- related deaths.1 The primary reasons for the high
mortality rate among ovarian cancer patients are the lack
of effective treatment options due to drug resistance and
the absence of early specific symptoms.2 Currently, the
standard therapy for ovarian cancer involves debulking
surgery combined with platinum- based chemotherapy.3
Although first- line treatment regimens are typically
effective, patients often experience significant side ef-
fects during chemotherapy. Additionally, some patients
become insensitive to chemotherapy due to drug resis-
tance.4 Therefore, the urgent clinical need is to seek new
chemotherapy regimens with fewer side effects or to find
new therapeutic drugs to enhance chemotherapy sen-
sitivity when combined with traditional chemotherapy
regimens.
Autophagy is a cellular catabolic process with cellular
protective functions. This process delivers damaged intra-
cellular proteins and organelles to lysosomes for degrad-
ing and recycling, provides energy and macromolecular
precursors,5 and supports nutrient recycling and meta-
bolic adaptation to promote cancer cell survival.6 Cellular
stress refers to the influence of various factors, including
oxidative stress, endoplasmic reticulum stress, hypoxia,
and nutrient limitations, on cells, leading to instability
in the internal environment.7–9 As an adaptive and self-
protective process, autophagy responds to various cyto-
toxic insults caused by cellular stress and prevents cell
damage to survive in these adverse environment.7,8,10
The activation of this protective autophagic process often
plays an important role in resisting the development of
resistance during cancer radiotherapy, chemotherapy, or
targeted therapy.11,12 Therefore, in recent years, autoph-
agy is regarded as an important pharmacological target
for cancer drug development and therapeutic interven-
tion, aiming to enhance treatment efficacy or counteract
treatment resistance.
Natural products derived from the natural world, such
as plants, fungi, and marine organisms, due to their low
extraction cost, high bioavailability, and ability to signifi-
cantly enhance cancer chemotherapy sensitivity or reduce
chemotherapy side effects, have attracted widespread at-
tention.13 In recent literature, natural products have been
reported to influence different regulatory components of
the autophagy pathway, such as mTOR, Beclin1, ATG7,
and others.14 In addition, the ability of natural products
to regulate cellular stress in cancer treatment has also gar-
nered increasing attention in recent years.15 Existing evi-
dence indicates that certain natural products can mitigate
the effects of oxidative stress,16 endoplasmic reticulum
stress,17 hypoxia,18,19 and starvation on cells.20 However,
a key issue that remains to be clarified is understanding
how they alter the autophagy process mediated by internal
cellular stress conditions and inhibit cancer progression.21
The primary goal of this paper is to comprehensively
examine the relationship between autophagy and various
stress responses in ovarian cancer and how natural prod-
ucts influence autophagy by modulating cellular stress
conditions and their potential impacts on ovarian cancer
treatment. By delving into this mechanism, we can bet-
ter understand the biological functions of natural prod-
ucts and their potential pharmaceutical applications,
providing a scientific basis for developing new treatment
strategies.
2
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MECHANISMS OF OVARIAN
CANCER PATHOGENESIS,
EPIDEMIOLOGY, AND CURRENT
TREATMENT STATUS
Ovarian cancer (OC) is one of the most common malig-
nant tumors worldwide and is the leading cause of death
from gynecological malignancies. In the early stages of
development, ovarian cancer patients often exhibit non-
specific symptoms such as bloating and pain, loss of ap-
petite, or increased urinary frequency. It is not until the
later stages that patients present with abdominal swelling
due to the accumulation of ascites.22 Due to the lack of re-
liable early diagnostic methods, tumor heterogeneity, and
the high incidence of chemotherapy resistance, the 5- year
natural products as valuable resources in cancer therapeutics, highlighting the
need for further exploration of their potential in regulating autophagy. Moreover,
it provides novel insights and potential therapeutic strategies in ovarian cancer by
utilizing natural products to modulate autophagy.
KEYWORDS
autophagy, natural products, ovarian cancer, stress
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LI etal.
survival rate for patients with advanced OC remains very
low.23
Due to the fact that ovarian cancer is not a single disease
but rather consists of different types of tumors with het-
erogeneity, it exhibits a wide range of clinicopathological
characteristics and behaviors. Ovarian cancer is currently
classified histologically into four types: epithelial tumors,
germ cell tumors, sex cord- stromal tumors, and metastatic
tumors. Among them, epithelial ovarian cancer (EOC) is
a type of cancer originating from the tissue covering the
ovary, accounting for 85%–90% of OC cases. Based on a se-
ries of morphological and molecular genetic studies, a bi-
nary classification model for EOC has been proposed.24,25
Type I tumors include low- grade serous tumors, low- grade
endometrioid tumors, clear cell carcinoma, and mucinous
carcinoma. They are associated with mutations in KRAS,
BRAF, PTEN, PIK3CA, CTNNB1, ARID1A, and PPP2R1A.
These tumors are generally indolent, confined to the ovary,
and typically have low sensitivity to chemotherapy.26 Type
II tumors include high- grade serous carcinoma, high- grade
endometrioid carcinoma, undifferentiated carcinoma,
and malignant mixed mesodermal tumors. These tumors
are clinically aggressive, often presenting with significant
symptoms at an advanced stage, which contributes to a
high mortality rate.27 Genomic instability and mutations
in TP53 (96%) and BRCA1/2 (22%) are common character-
istics of high- grade serous ovarian cancer (HGSC). Among
the histological subtypes, the serous subtype is the most
common and the most aggressive, accounting for 70% of
epithelial ovarian cancers (EOC).28 Recent studies have
identified secretory cells at the fimbriae of the fallopian
tubes as the cells of origin for high- grade serous carcinoma.
These secretory cells in the fimbriae accumulate TP53 mu-
tations under the influence of reactive oxygen species from
follicular fluid and hemoglobin from retrograde menstru-
ation. The continuous stimulation from growth factors in
ovulatory follicular fluid leads to the formation of “p53
signature lesions.” Subsequently, due to the loss of proges-
terone receptors, the failure of homologous recombination
repair proteins (BRCA1/2), and the continuous production
of mutagens and growth factors resulting from repeated
ovulation, these lesions eventually progress to serous tubal
intraepithelial carcinoma. This carcinoma then metas-
tasizes to the ovaries, presenting as clinically significant
ovarian cancer.29
Currently, the treatment for ovarian cancer (OC)
primarily involves cytoreductive surgery and adjuvant
chemotherapy, with chemotherapeutic drugs including
platinum- based agents such as cisplatin or carboplatin
combined with taxanes (typically paclitaxel). Cisplatin in-
teracts with deoxyguanosine and deoxyadenosine to form
intrastrand and interstrand cross- links, thereby affecting
DNA replication and transcription and promoting cell
death. Paclitaxel, on the other hand, induces cell death by
preventing the depolymerization of microtubules through
interaction with the β- subunit of tubulin.30,31 However,
some patients develop acquired chemoresistance at the
end of chemotherapy or exhibit intrinsic chemoresistance,
which is mainly associated with DNA methylation, histone
modifications, and non- coding RNA activity. Therefore,
finding new therapeutic targets is of great value.32 With
the increasing use of various new drugs, resistance has also
emerged to angiogenesis inhibitors and immunosuppres-
sants, posing significant challenges for the development
of second- line treatments. The four major mechanisms
of resistance—transmembrane transport abnormalities,
altered DNA damage repair, dysregulated cancer- related
signaling pathways, and epigenetic modifications—are
interconnected. Identifying intersections among these re-
sistance mechanisms could potentially open new avenues
for treating OC.33
3
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AUTOPHAGY
3.1
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Definition and mechanism of
autophagy
Autophagy, a protein degradation system within eukar-
yotic cells, is crucial for maintaining cellular metabo-
lism and energy balance. It breaks down proteins, lipids
(through lipophagy), carbohydrates (via glycophagy),
and iron (ferritinophagy), thereby supplying fuel to sus-
tain cellular energy and store nutrients.34 Under normal
circumstances, cells utilize basal levels of autophagy
to aid in maintaining biological functions, homeosta-
sis, and the quality of cellular contents. Currently, au-
tophagy is classified into three types: macroautophagy,
microautophagy, and chaperone- mediated autophagy.
Macroautophagy involves the formation of autophago-
somes around materials destined for degradation, such
as endoplasmic reticulum, Golgi apparatus, or cytoplas-
mic membranes. Initiation of autophagosome forma-
tion relies on the activation of the ULK1 (also known
as ATG1) complex, consisting of ULK1, ULK2, ATG13,
and FIP200. This complex activates the Class III PI3K
complex (including VPS15, VPS34, ATG14, Beclin1),
which in turn activates autophagy through the regula-
tion of BECLIN1- associated autophagy- related protein
1 (AMBRA1). Subsequently, the ATG5- ATG12 complex
couples with ATG16 to facilitate expansion of the au-
tophagosomal membrane, while the binding of ATG4
with ATG7 and ATG3 converts LC3- I into LC3- II (also
known as MAP1LC3B), thereby elongating the vesicles
and promoting autophagosome maturation. Ultimately,
autophagosomes fuse with lysosomes, where their
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contents are degraded, and large molecular precursors
are either recycled or utilized to provide fuel for meta-
bolic pathways. Simultaneously, mTORC1 (mechanis-
tic target of rapamycin complex 1) also plays a crucial
role in autophagy regulation.5 Microautophagy involves
direct envelopment of long- lived proteins and other
substances by the membrane of lysosomes, followed by
degradation within the lysosomal lumen. Chaperone-
mediated autophagy (CMA), on the other hand, exhibits
high substrate selectivity, where cytosolic proteins bind
to molecular chaperones and are then transported into
the lumen of lysosomes for subsequent degradation by
lysosomal enzymes.35,36 The process of autophagy can be
divided into five distinct stages: initiation, vesicle nuclea-
tion, vesicle elongation, vesicle fusion, and degradation
and recycling (Refer to Figure1).
3.2
|
Specific targets affecting ovarian
cancer progression by regulating
autophagy
Autophagy in ovarian cancer is regulated by numerous
oncogenic or tumor- suppressive molecules, each impact-
ing ovarian cancer progression in various ways. Among
them, mTOR is the most critical regulatory target in
ovarian cancer autophagy, playing a central role in me-
diating the effects of multiple molecules on autophagy.
The downregulation of the low- density lipoprotein re-
ceptor (LDLR) inhibits autophagy and growth in DDP-
resistant OC cell lines by activating the PI3K/AKT/
mTOR pathway.37 CircEEF2 (has- circ- 0048559) directly
binds to ANXA2, suppresses p- mTOR expression, and
promotes the expression of ATG5 and ATG7, thereby
FIGURE Cells regulate the process of autophagy through multiple signaling pathways when under stress. Among them, the PI3K/
Akt signaling pathway and the MAPK signaling pathway play crucial roles in regulating the activity of mTORC1. When cells are under
stress, these signaling pathways can inhibit the expression of mTORC1, activating the process of autophagy. Additionally, the class III PI3K
complex is also activated, further promoting autophagy. During the execution phase of autophagy, the ATG5- ATG12- ATG16L1 complex and
the conversion of LC3 to LC3- II are important steps in the expansion of the autophagosomal membrane. These two pathways work together
to promote the formation and maturation of autophagosomes. Ultimately, autophagosomes fuse with lysosomes, where their contents are
degraded by hydrolases, providing nutrients and energy for the cell or recycling macromolecular precursors to participate in metabolic
pathways. This process is of significant importance for maintaining cellular homeostasis and responding to various stress conditions.
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activating autophagy and enhancing the proliferation
and invasion of EOC.38 In ovarian cancer cells, knock-
ing down HIF- 1α inhibits the PI3K/AKT/mTOR signal-
ing pathway, promotes autophagy, and reduces ovarian
cancer cell viability.39 Plakophilin 3 (PKP3) activates the
MAPK- JNK- ERK1/2- mTOR signaling pathway, inhibits
autophagy, and promotes cell proliferation and invasion
in ovarian cancer.40 The ubiquitin- conjugating enzyme
E2S (UBE2S) suppresses autophagy by activating the
PI3K/AKT/mTOR signaling axis, leading to cisplatin
resistance in ovarian cancer.41 ATPase H- Transporting
V1 Subunit B1 (ATP6V1B1) enhances the expression
of mTOR protein in ovarian cancer cells, blocks au-
tophagy, promotes proliferation, migration, and inva-
sion, and reduces sensitivity to cisplatin.42 The family
with sequence similarity 83, member D (FAM83D) in-
hibits autophagy by activating the PI3K/AKT/mTOR
signaling pathway, thereby promoting ovarian cancer
cell invasion and proliferation.43 UBE2T upregulation
in ovarian cancer activates AKT/mTOR suppresses au-
tophagy and induces epithelial- mesenchymal transition
(EMT), ultimately promoting the proliferation and inva-
sion of ovarian cancer cells.44 HERPUD1 inhibits EMT
and the PI3K/AKT/mTOR and p38MAPK pathways,
promoting autophagy, which enhances cell prolifera-
tion and inhibits apoptosis in ovarian cancer cells.45 The
downregulation of lysine- specific demethylase 1 (LSD1)
induces autophagy by inhibiting mTOR signaling, sug-
gesting that LSD1 may drive ovarian cancer progression
through autophagy deregulation.46 The E3 ubiquitin
ligase F- box only protein 22 (FBXO22) suppresses au-
tophagy through the activation of the MAPK/ERK path-
way, promoting the growth and metastasis of epithelial
ovarian cancer.47 ALKBH5 activates the EGFR- PIK3CA-
AKT–mTOR signaling pathway and enhances the stabil-
ity of BCL- 2 mRNA, promoting the interaction between
Bcl- 2 and Beclin1, ultimately facilitating ovarian cancer
proliferation and migration.48
Beclin- 1 acts as a molecular scaffold for assembling
the PI3KC3 complex, playing a crucial regulatory role in
autophagy and influencing drug resistance and the main-
tenance of cancer stemness.49 CircRNF144B increases
FBXL11 levels by sponging miR- 342- 3p, and the elevated
FBXL11 promotes the ubiquitination and degradation of
Beclin- 1, thereby inhibiting autophagy and promoting
OC progression.50 LncRNA GAS8- AS1 inhibits OC pro-
gression by binding to Beclin1 and activating autophagy.51
DIRAS3 can bind to Beclin1 in ovarian cancer, forming
the autophagy initiation complex, triggering autophago-
some formation, and inhibiting cancer cell proliferation
and motility.52 Chromatin immunoprecipitation (ChIP)
experiments revealed that lncRNA RNF157 Antisense
RNA 1 (RNF157- AS1) and HMGA1 bind to the ULK1
promoter, preventing ULK1 expression. Additionally,
RNF157- AS1 interacts with EZH2, binding to the DIRAS3
promoter and decreasing DIRAS3 expression. The inhibi-
tion of autophagy increases the sensitivity of EOC cells to
the chemotherapeutic drug cisplatin (DDP).53 CUL3 (cul-
lin 3), as an E3 ubiquitin ligase, promotes the ubiquitina-
tion and degradation of Beclin1, downregulating BECN1
expression, which reduces autophagic activity and pro-
motes proliferation in ovarian and breast cancer.54 PD- L1
promotes autophagy and proliferation in ovarian cancer
cells by upregulating BECN1 expression.55 CircMUC16
can directly bind to miR- 199a- 5p, relieving its inhibi-
tion of Beclin1 and RUNX1. Additionally, CircMUC16
can also directly bind to ATG13 and promote ATG13
expression, enhancing autophagic flux in A2780 cells and
exacerbating the invasion and metastasis of EOC.56
A series of ATG proteins are highly involved in
the initiation of autophagy and the assembly of au-
tophagosomes, playing crucial roles in autophagy.57
CircRAB11FIP1 promotes the expression of ATG7 and
ATG14 by sponging miR- 129, activating autophagy,
and accelerating EOC proliferation and invasion.58
MARCH5 RNA functions as a competing endogenous
RNA (ceRNA), regulating the expression of SMAD2
and ATG5 by competing with MIR30A binding, thereby
promoting autophagy, migration, and invasion in ovar-
ian cancer cells.59 The overexpression of miR- 29c- 3p
partially inhibits autophagy and increases sensitivity
to DDP by suppressing the Forkhead box protein P1
(FOXP1)/ATG14 pathway, indicating that miR- 29c- 3p is
a novel target for overcoming DDP resistance in ovar-
ian cancer.60 Additionally, some molecules regulate
autophagy in ovarian cancer by mediating lysosomal
function. Overexpression of PNPO enhances lysosomal
biogenesis and perinuclear distribution, promoting au-
tophagosome degradation and increasing autophagic
flux. Moreover, the autolysosomal marker LAMP2 is
upregulated in OC cells, ultimately reducing the sen-
sitivity of ovarian cancer cells to paclitaxel.61 Under
cisplatin treatment conditions, the downregulation
of OGT induces the formation of the SNAP29- Stx17-
VAMP8 complex, mediating the fusion of autophago-
somes and lysosomes, promoting autophagic flux, and
enhancing cisplatin resistance in ovarian cancer (Refer
to Figure2).62
3.3
|
Autophagy regulates various
malignant biological behaviors in
ovarian cancer
In ovarian cancer, autophagy regulation plays a dual role
in tumor suppression and promotion, closely intertwined
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with its biological behaviors (Figure2). Many mecha-
nisms within autophagy regulation likely influence
early stages of tumor occurrence and progression, in-
cluding removal of ROS- damaged mitochondria, deg-
radation of oncogenic viruses, maintenance of genomic
stability, and promotion of oxidative phosphorylation
of stress- responsive enzymes.8,57,63 It is noteworthy that
an increasing amount of research indicates autophagy
supports the metabolic plasticity of cancer cells by de-
grading carbohydrates, proteins, and lipids for energy
metabolism, ensuring cancer cell survival during nutri-
ent deprivation and dormancy states.64 Meanwhile, pro-
tective autophagy in cancer cells can inhibit apoptosis
and increase their resistance to drugs.8 Simultaneously,
autophagy plays a role in DNA damage repair, protect-
ing the stability of the genome and proteome, thereby
exerting anticancer and preventive functions. However,
this process also contributes to repairing DNA damage
induced by anticancer drugs, thereby enhancing resist-
ance of OCs and complicating the cure of OC (Refer to
Figure3).35,65
4
|
NATURAL PRODUCTS
REGULATE AUTOPHAGY TO
CONTROL THE MALIGNANT
BIOLOGICAL BEHAVIORS OF
OVARIAN CANCER
4.1
|
Natural products have been
reported to treat ovarian cancer
Although debulking surgery combined with postoperative
platinum/taxane chemotherapy is the current standard
first- line treatment and generally effective, the side effects
and chemotherapy resistance associated with chemother-
apy significantly limit the efficacy of conventional treat-
ment regimens. Therefore, finding new therapeutic drugs
to improve chemotherapy resistance or reduce side effects
to enhance efficacy is urgently needed. Natural products,
characterized by high bioavailability, low cost, and broad
pharmacological effects, have attracted attention. In recent
years, natural products have been reported for use in initial
treatment or maintenance therapy, improving multidrug
FIGURE Specific targets regulating autophagy in ovarian cancer.
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LI etal.
sensitivity, inhibiting tumor growth, and metastasis.66
Several studies have shown that natural products can in-
hibit the progression of ovarian cancer by affecting various
biological behaviors: Zeylenone, Sanguiin H- 6, Berbamine,
resveratrol, and curcumin have been reported to inhibit
ovarian cancer cell proliferation or promote apoptosis67–70;
tetramethylpyrazine, dihydroartemisinin, and emodin
have been reported to inhibit ovarian cancer invasion
and migration, thus suppressing ovarian cancer progres-
sion.71–73 Quercetin and formononetin have been reported
to mediate ROS production in ovarian cancer cells, exert-
ing toxic effects.74,75 Cucurbitacin- A, Amentoflavone, and
Isoliquiritigenin have been reported to induce cell cycle ar-
rest in ovarian cancer cells, thereby inhibiting malignant
progression76–78; Chinese bayberry leaves proanthocya-
nidin, Tan- IIA have been reported to inhibit angiogen-
esis invitro and suppress ovarian cancer progression79,80;
Tanshinone I, grifolin, genistein, and isoliquiritigenin
have been reported to induce cell death by affecting au-
tophagy.81–84 Ellagic acid, resveratrol, Korean dark rasp-
berry, and WFA have been reported to inhibit platinum or
paclitaxel resistance in ovarian cancer cells.85–87 In sum-
mary, natural products can inhibit ovarian cancer pro-
gression by suppressing proliferation, migration, invasion,
angiogenesis, and resistance; regulating autophagy and
ROS production; promoting cell cycle arrest and apoptosis.
4.2
|
Natural products can act on
different stages of autophagy to exert their
pharmacological effects
Natural products are important sources for the discovery
of biologically active substances and practical medicines.
FIGURE The formation of phagophores, the maturation of autophagosomes, and the degradation within lysosomes are integral
processes throughout autophagy. Autophagy exhibits a dual role in the initiation and progression of tumors. In the early stages of
tumorigenesis, autophagy serves as a tumor- suppressive mechanism by removing damaged mitochondria, degrading oncogenic viruses,
maintaining genomic stability, and promoting the oxidative phosphorylation of critical enzymes involved in stress responses, thus inhibiting
cancer. However, autophagy can also act as a pro- tumorigenic factor by providing energy metabolism for cancer cells, aiding their survival
in nutrient- deprived environments, thereby reducing apoptosis, promoting cancer initiation and progression, and enhancing resistance to
drugs, thus improving their survival capabilities.
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Research has found that unmodified natural products,
botanical drugs, and derivatives thereof constitute over
53% of anticancer drugs. This indicates that natural prod-
ucts have enormous potential for exploration in the field
of cancer treatment.97 As mentioned above, autophagy,
as a unique physiological mechanism in cells, can exert
protective or destructive effects in disease states. Precisely
identifying and developing drugs targeting this cellular
process will contribute to disease treatment. Researchers
have discovered various natural compounds that can in-
hibit or induce autophagy at different stages.98
Autophagy consists of five stages: initiation/nucle-
ation, elongation, maturation, fusion, and degradation/
recycling, as illustrated in Figure1. The initiation and
nucleation of autophagosomes rely on the generation
of the Class III PI3K complex and the ULK1/2 com-
plex.99 Therefore, inhibitors of Class III PI3K complex,
such as the natural product wortmannin and its analog
3- methyladenine (3- MA), exert their effects during the
initiation stage of autophagy by suppressing the activ-
ity of the Class III PI3K complex. They are recognized
as early- stage autophagy inhibitors.14,100–102 In natu-
ral products, compounds like rapamycin (a macrolide
antibiotic) can act as autophagy inducers, functioning
specifically as inhibitors of mTORC1 at the initiation
and nucleation stages of autophagosome formation.103
Quercetin and resveratrol are flavonoids that can acti-
vate AMPK signaling pathways, initiating and nucle-
ating autophagy to protect the body.104–107 In addition,
gamma- tocotrienol can also activate AMPK, initiating
and nucleating autophagy, increasing the expression lev-
els of LC3- II, ATG5, and Beclin1, thereby promoting the
process of autophagy.108
Natural products also participate in regulating
the elongation and maturation stages of autophagy.
Vincristine and its derivative vinblastine, as targeted
therapies for malignant tumors, primarily act by re-
ducing the efficiency of LC3- I to LC3- II conversion,
decreasing the production of the autophagy marker
p62, thereby promoting their anticancer activity by in-
hibiting the formation and maturation of autophago-
somes.109 Anti- aggregation drugs such as colchicine and
N- acetyl- L- cysteine, as microtubule- binding agents,
inhibit their aggregation in tumor cells to prevent the
formation of autophagosomes.110 Qi compounds like
Danshensu B and natural fisetin compounds can also
affect the elongation of autophagic vesicles by inhibit-
ing LC3 lipidation.111,112 Curcumin increases the tran-
scriptional activity of TFEB, thereby inhibiting mTOR
and increasing LC3 levels to activate autophagy.113
Some literature reports that natural products can
also regulate the fusion stage of autophagosomes and
exert pharmacological activities. For example, mon-
ensin and nigericin interfere with the fusion of auto-
phagosomes with lysosomes, inhibiting the autophagic
process at this stage.114 Similarly, liensinine disrupts
the recruitment of small GTPase RAB7A to lysosomes,
inhibiting the transport of endocytic proteases to lyso-
somes, thus suppressing autophagosome- lysosome fu-
sion.115 Additionally, several natural compounds have
been discovered to act on the late- stage degradation
process of autophagy, including lysosomal proliferators
(QC), vacuolar- type ATPase inhibitors (Baf A1), and ly-
sosomal protease inhibitors (pepstatin A), which inhibit
lysosomal enzymes from degrading autophagosomes,
thereby exerting antitumor activity by inhibiting auto-
phagy (Figure4).116,117
4.3
|
Natural products also participate
in regulating autophagy to inhibit the
progression of ovarian cancer
Currently, natural products have been proven to af-
fect autophagy processes, and their therapeutic effects
on ovarian cancer have been confirmed by numerous
researchers. There is extensive evidence demonstrat-
ing that natural products can suppress the malignant
biological behaviors of ovarian cancer by activating
autophagy. Epoxycytochalasin H has been reported to
induce mitochondrial damage and activate autophagy
and mitophagy in A2780 cells, subsequently inducing
cell apoptosis through the mitochondrial pathway.88
Suberoylanilide hydroxamic acid combined with pacli-
taxel can promote autophagy to inhibit ovarian cancer
cell migration.89 Ellagic acid inhibits mTORC1 and Akt,
activates AMPK, and triggers cytotoxic autophagy to
inhibit the growth, migration, and invasion of SKOV3
cells.92 In ovarian cancer, Pardaxin induces excessive re-
active oxygen species production in cells and mitochon-
dria, activating autophagy and mitophagy, and leading
to mitochondria- mediated cell apoptosis.93 Matrine at-
tenuates Akt/mTOR signaling to activate autophagy
in ovarian cancer cells and inhibits proliferation, in-
vasion, migration, and angiogenesis while promoting
apoptosis.94 Damnacanthal activates autophagy to in-
hibit ovarian cancer cell proliferation and migration.95
Astragaloside II activates autophagy and inhibits the
growth of cisplatin- resistant ovarian cancer cells both
invivo and invitro, promoting apoptosis.96 Additionally,
natural products have been reported to suppress ovarian
cancer progression by inhibiting autophagy: Elaiophylin
acts as an autophagy inhibitor, promoting autophago-
some accumulation but reducing lysosomal protease
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LI etal.
activity, blocking autophagic flux, inhibiting cell vi-
ability, inducing cell death, suppressing insitu cancer
metastasis, and sensitizing cells to cisplatin's antitumor
effects invitro.90 Nobiletin enhances apoptosis and in-
hibits autophagy in multidrug- resistant SKOV3/TAX
cells.91 In conclusion, natural products can control the
FIGURE The regulatory effects of natural products on autophagy.
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LI etal.
progression of ovarian cancer by regulating autophagy
(Table1).
5
|
NATURAL PRODUCTS
CAN TREAT OVARIAN CANCER
BY CONTROLLING STRESS
RESPONSE- MEDIATED
AUTOPHAGY
5.1
|
Stress response activates autophagy
5.1.1
|
Endoplasmic reticulum stress and
autophagy
Endoplasmic reticulum stress (ERS) is a common cellular
stress phenomenon involving imbalance in the endoplas-
mic reticulum caused by various genetic and environ-
mental insults. The endoplasmic reticulum serves as a
site for folding of secretory and transmembrane proteins,
where they attain three- dimensional structure and un-
dergo post- translational modifications.118,119 Changes in
intracellular ER Ca2+ levels, accumulation of misfolded
or mutant proteins, or glucose restriction can impair the
ability of cells to correctly fold and modify secretory and
transmembrane proteins in the endoplasmic reticulum
(ER), leading to calcium depletion and disruption of lipid
synthesis, ultimately causing endoplasmic reticulum
stress.120 ERS triggers evolutionarily conserved cascade
reactions known as the unfolded protein response (UPR)
to counteract the harmful consequences of endoplasmic
reticulum stress and help restore endoplasmic reticulum
homeostasis; failure to counteract it can activate cellular
apoptosis.121
The connection between UPR and autophagy
When improperly folded or misfolded proteins accumulate
beyond a critical threshold, the unfolded protein response
(UPR) pathway is activated, executed by three main pro-
teins and their downstream effectors: inositol- requiring
enzyme 1 alpha (IRE1α), protein kinase R- like endoplas-
mic reticulum kinase (PERK), and activating transcrip-
tion factor 6 alpha (ATF6α). The forward endoplasmic
reticulum stress response is initiated by oligomerization
TABLE Natural products regulate autophagy to inhibit ovarian cancer progression.
Drug name
Ovarian
cancer cell
lines
Impact on autophagy
molecules
Effects on
autophagy
Impact on which
malignant biological
behaviors of ovarian
cancer References
Epoxycytochalasin
H
A2780 LC3- II/LC3- I ratio
increases, P62 expression
increases
Activates autophagy Promotes apoptosis [88]
Suberoylanilide
hydroxamic acid
OC3/P Increased number of
autophagosomes
Activates autophagy Inhibits migration [89]
Elaiophylin SKOV3 Increased expression of P62
and LC3B- II
Inhibits autophagy Enhances sensitivity
to cisplatin, inhibits
insitu cancer metastasis,
reduces cell viability
[90]
Nobiletin SKOV3/TAX Increased expression of
LC3BII and P62
Inhibits autophagy Promotes apoptosis,
inhibits multidrug
resistance
[91]
Ellagic acid SKOV3 Increased Beclin- 1, ATG- 5,
LC3I/II, decreased P62
Activates autophagy Inhibits proliferation,
migration, invasion
[92]
Pardaxin PA- 1, SKOV3 Increased expression of
Beclin, p62, LC3
Activates autophagy Promotes apoptosis [93]
Matrine A2780, SKOV3 Increased expression
of LC3II, decreased
expression of P62
Activates autophagy Inhibit migration and
invasion
[94]
Damnacanthal A2780, SKOV3 Increased expression
of LC3II, decreased
expression of P62
Activates autophagy Promote apoptosis,
inhibit cell viability and
migration
[95]
Astragaloside II SKOV3,
SKOV3/DDP
Increased expression
of LC3II, decreased
expression of P62
Activates autophagy Promote apoptosis,
enhance sensitivity to
DDP
[96]
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LI etal.
of IRE1α and PERK, which can activate stress- activated
kinase p38 MAPK, thereby upregulating the expression
of UPR genes.122 ATF6α, a member of the ATF6 family,
promotes the expression of ER quality control genes by
recruiting regulated transcription coactivator 2 (CRTC2)
to ER stress response elements in gene promoters.123
Overall, these three pathways interact to maintain ER ho-
meostasis, alleviating endoplasmic reticulum stress dur-
ing acute or mild stress.124
All three branches of the UPR can influence autoph-
agy activation: IRE1α is considered a central regulator
necessary for autophagy activation.125,126 Upregulation of
GRP78, IRE1α, and LC3B during ER stress leads to can-
cer cell tolerance to tunicamycin.127 IE1α affects autoph-
agy processes by cleaving XBP1 mRNA to influence the
binding of FOXO1 with ATG7 and can also promote auto-
phagy by affecting Bcl2 protein phosphorylation through
the TRAF2/ASK1/JNK pathway, thereby influencing its
dissociation from Beclin- 1.127–130 The PERK branch can
regulate the formation of autophagosomes during ER
stress by modulating LC3II and ATG12- ATG5.131 PERK
upregulates microtubule- associated protein 1 light chain
3 beta (MAP1LC3) and autophagy protein 5 (ATG5) tran-
scriptionally through ATF4 and CHOP to promote auto-
phagosome formation under hypoxia.132,133 Additionally,
during ER stress, PERK activation leads to adaptive resis-
tance through autophagy induction via eIF2α phosphor-
ylation and ATF4- dependent ATG12 activation.134 ATF6
can activate autophagy and promote cancer cell survival
by upregulating LC3B expression.135 ATF6's transcrip-
tional activity can also activate autophagy by overex-
pressing HSPA5.136 ATF6 regulates autophagy of dormant
tumor cells through the ATF6- Rheb- mTOR pathway to
restore resistance to rapamycin.137 Endoplasmic retic-
ulum stress can also influence mTORC1 dephosphory-
lation and ULK activation through AMPK activation to
promote autophagy.135
Non- classical endoplasmic reticulum stress and
autophagy
Atypical endoplasmic reticulum stress (ERS) represents
additional pathways that activate the unfolded protein
response (UPR), linking cellular stress to ER stress and
autophagy, and leading to the transcription of certain au-
tophagy genes and upregulation of autophagy flux.135,138
These atypical ER stress responses include the integrated
stress response (ISR), ER translocation and ERK reacti-
vation, ER- associated protein degradation (ERAD), and
ER- autophagy.138 The core of ISR involves the phosphoryl-
ation of eIF2α, controlled by PERK, PKR, GCN2, and HRI,
playing a crucial role in the adaptive survival mechanisms
of human malignancies.138 In MYC- driven cancers, the
activation of MYC increases the synthesis of ERS- related
proteins. As a response, PERK- mediated phosphoryla-
tion of eIF2α limits the rate of protein translation and
activates prosurvival autophagy to avoid proteotoxicity
during tumor growth.139 Additionally, during amino acid
starvation, GCN2 is activated by uncharged tRNA, lead-
ing to the phosphorylation of eIF2α and promoting the
expression of ATF4 in MYC- driven cancers.140 ER trans-
location and ERK reactivation refer to the translocation
of the MAPK protein complex from the cytoplasm to the
ER lumen via the translocon Sec61. Subsequently, ERK
translocates back to the cytoplasm while other compo-
nents of the MAPK complex, such as NRAS, BRAF, and
MEK, remain in the ER. Once in the cytoplasm, ERK is
phosphorylated and reactivated by PERK. This reactivated
ERK then phosphorylates ATF4, which, as a transcription
factor, upregulates multiple autophagy genes, thereby ac-
tivating autophagy.138,141 Furthermore, misfolded proteins
are translocated from the ER lumen to the cytoplasm via
the translocon Sec61, where they undergo ubiquitination
and degradation, a process known as ERAD. Misfolded
proteins that cannot be degraded by ERAD are delivered
to endo- lysosomal compartments and partially degraded
via autophagy pathways. During severe ER stress, ER-
autophagy is activated, selectively engulfing the ER into
autophagosomes to restore ER homeostasis and promote
cell survival.142,143
ER stress response activates autophagy in ovarian
cancer
Studies indicate that ERS- induced autophagy can pro-
tect cells. UPR, as a typical ERS, promotes the degra-
dation of unfolded and/or misfolded proteins through
autophagy, restoring cellular homeostasis and partici-
pating in various biological processes closely related to
cell apoptosis in OC, such as increased ROS produc-
tion, mitochondrial dysfunction, DNA damage, resist-
ance, autophagy, cell cycle, and aging.144 HERPUD1, as
an important early marker of endoplasmic reticulum
stress (ERS), promotes OC cell proliferation, inhibits
apoptosis, induces autophagy, and suppresses EMT,
PI3K/AKT/mTOR, and p38- MAPK pathways.45 The
inhibitor of DNA binding 1 (ID1) induces endoplas-
mic reticulum stress by activating the STAT3/ATF6
axis, thereby promoting autophagy and conferring re-
sistance to cisplatin and paclitaxel treatment in ovar-
ian cancer cells.145 Furthermore, ubiquitin- binding
protein p62/SQSTM1 (sequestosome 1) is abundant
in cisplatin- resistant SKOV3 cells in OC, inhibiting
ERS- and autophagy- mediated cell apoptosis, thereby
increasing tumor cell resistance to cisplatin.146,147 Tang
et al. demonstrated that autophagy protects BRCA1-
deficient cancer cells from ERS damage and promotes
OC progression.148
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5.1.2
|
Hypoxia can activate autophagy in
several histological types of ovarian cancer
During the advanced stages of tumor growth, tumor cells
situated in hypoxic regions can employ autophagy to
sustain survival under conditions of nutrient scarcity or
hypoxia.149 Thus, hypoxia- mediated autophagy modula-
tion is also considered a crucial target in ovarian cancer
therapy. Research has shown that ovarian clear cell carci-
noma exhibits higher levels of autophagy under hypoxic
conditions, which is associated with the development of
drug resistance and lower survival rates in patients.150,151
Similar findings have been confirmed in PA- 1 ovarian ter-
atoma cells, where autophagy is activated under hypoxia,
inhibiting cisplatin- induced apoptosis and increasing
chemotherapy resistance.152 Additionally, human omen-
tal adipose- derived stem cells (ADSCs) can play a similar
role in the malignant progression of ovarian cancer: Under
hypoxic conditions, human omental ADSCs activate the
STAT3 signaling pathway to promote autophagy, thereby
enhancing the proliferation and invasion of ovarian cancer
cells.153 These findings suggest that hypoxia can activate
autophagy in various histological types of ovarian cancer
and influence its malignant progression. As tumor tissues
grow, hypoxia often ensues, accompanied by heightened
expression of hypoxia- inducible factor 1 alpha (HIF- 1α).
This hypoxic environment fosters the formation of oxygen
concentration gradients within the tumor, which in turn
promotes tumor cell heterogeneity and facilitates tumor
invasion and metastasis.154 Therefore, HIF- 1α is consid-
ered a crucial target under hypoxic conditions, and its
regulation of autophagy has received extensive research
attention. Hypoxia- induced DDP resistance is associated
with HIF- 1α- induced autophagy.155 Baohuoside I (derived
from Herba Epimedii) inhibits autophagy by downregu-
lating the HIF- 1α/ATG5 axis, sensitizing ovarian cancer
cells to DDP invivo.156 Moreover, investigations suggest
that HIF- 1α and HDAC4 mediate the interaction between
p53 and RAS signaling, actively regulating cisplatin resist-
ance in ovarian cancer through apoptosis and dysregula-
tion of autophagy.157 In summary, numerous studies have
shown that the regulation of autophagy by HIF- 1α influ-
ences drug resistance in ovarian cancer.
5.1.3
|
Starvation and autophagy
Autophagy serves to degrade stored proteins, lipids, and
glycogen during periods of cellular nutrient scarcity to
generate energy, thus maintaining nutritional balance
and supporting normal cellular functions. Changes in in-
tracellular amino acid levels activate autophagy, which,
through protein hydrolysis, maintains the amino acid
pool to uphold intracellular amino acid homeostasis. The
mammalian target of rapamycin complex 1 (mTORC1)
stands as a pivotal molecule in regulating this amino acid
homeostasis. Under conditions of abundant amino acids,
the v- ATPase–Regulator–Rag GTPase complex activates
mTORC1, leading to the inhibition of ULK1 and Beclin- 1–
Vps34 complexes, thereby suppressing autophagy.
Conversely, under amino acid deprivation, these path-
ways are deactivated, thereby inducing autophagy.158–160
For example, under starvation conditions, the inacti-
vation of mTOR triggers the biological invasiveness of
ovarian cancer (OC) by affecting the ULK1- SH3PXD2A/
TKS5- MMP14 pathway.161 Glucose deprivation activates
autophagy through transcriptional or post- translational
modifications of autophagy- related genes. Under condi-
tions of glucose deprivation, cellular ATP levels decrease,
and the ATP/AMP ratio decreases, leading to the activation
of AMPK (5′- AMP- activated protein kinase) as an energy
sensor. AMPK is activated in response to decreased ATP
levels and increased AMP levels.162,163 Activated AMPK
phosphorylates RPTOR (a component of mTORC1) and
activates TSC2 (an inhibitor of mTORC1), thereby inhibit-
ing mTORC1 activity and inducing autophagy to generate
sufficient ATP through energy metabolism.162,163 When
glucose is deficient, DEPTOR (DEP domain- containing
mTOR- interacting protein) and hexokinase II (HKII) can
bind together to inhibit mTORC1, promoting autophagy
to regulate energy metabolism.164–166 In summary,
under conditions of amino acid and glucose deprivation,
mTORC1, as a central regulator, is widely inhibited, lead-
ing to the activation of autophagy.
Autophagy is activated under starvation conditions in
ovarian cancer cells, promoting malignant progression
Several clinical or basic studies have indicated that
starvation- induced autophagy affects the prognosis of
ovarian cancer patients. Literature demonstrates that
after the initial surgery or chemotherapy for OC, cancer
cells persist in poorly vascularized scars on the peritoneal
surface and rely on autophagy to survive in a starved en-
vironment.167 Lysine- specific demethylase 1 (LSD1) plays
a crucial role in cell proliferation, differentiation, and
carcinogenesis. Wei's team found that LSD1 inhibits au-
tophagy induced by serum starvation and rapamycin in
tumor cells through the mTOR signaling pathway, serv-
ing as a driving factor in the progression of OC.46 DIRAS3
mediates amino acid starvation- induced autophagy,
where mTOR plays a central role. Depletion of amino
acids leads to reduced mTOR expression, consequently
decreasing the binding of E2F1/4 to the DIRAS3 pro-
moter. This results in increased DIRAS3 expression and
induction of autophagy, thereby sustaining the survival of
dormant OCs.168 DIRAS3 expression in OC cells disrupts
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signaling through the PI3K and Ras/MAP pathways,
leading to mTOR downregulation and initiation of au-
tophagy. Furthermore, DIRAS3- mediated downregula-
tion of PI3K/AKT and Ras/ERK signaling also reduces
phosphorylation of FOXO3a (Forkhead box O3 protein),
causing FOXO3a to be sequestered in the cell nucleus,
inhibiting the expression of ATG4 and MAP- LC3- I, and
promoting autophagy.169 Che etal. found that depletion
of BRUCE promotes autophagy induction by reducing cel-
lular energy and activating the AMPK- ULK1- autophagy
axis, thereby enhancing chemotherapy resistance in ovar-
ian cancer.170 Additionally, it is noteworthy that the acti-
vation of LC3- II and p62- mediated autophagy in OCs is
crucial for the metastasis of OCs in the peritoneal micro-
environment under conditions of exposure to starvation
stress.171 In summary, the activation of autophagy under
starvation conditions plays a crucial role in the survival of
ovarian cancer cells.
5.1.4
|
The regulatory relationship between
oxidative stress and autophagy in ovarian
cancer is bidirectional
Reactive oxygen species (ROS) and reactive nitrogen spe-
cies (RNS) are byproducts of cellular metabolism and are
the main molecules responsible for oxidative stress.172
When the balance of ROS/RNS is disrupted and exceeds
the cell's own antioxidant capacity, cellular stress re-
sponses are activated to promote survival. However, if the
oxidative damage caused by the imbalance of ROS/RNS
cannot be repaired by endogenous mechanisms within
the cell, oxidative stress can lead to cell death.173–176
Autophagy is typically considered as a cellular adaptive
response that promotes cell survival by recycling damaged
cellular components to generate energy, thereby main-
taining cellular homeostasis under stress conditions.177,178
However, some literature reports suggest that autophagy
can lead to cell death by excessive degradation of essen-
tial components required for maintaining normal cellular
functions.179 Therefore, the relationship between oxida-
tive stress and autophagy, as well as the biological roles
played by both in cancer, is highly complex.
Under normal circumstances, oxidative stress in ovar-
ian cancer cells activates protective autophagy, thereby
promoting cancer cell survival. In low- grade ovarian can-
cer, typically characterized by KRAS mutations, DIRAS,
as an endogenous non- RAS protein, possesses inhibitory
functions on the growth of low- grade ovarian cancer cells.
However, in ovarian cancer cells with KRAS mutations,
DIRAS can accumulate ROS and induce oxidative stress
by inhibiting the RAS/MAPK/ERK signaling pathway,
paradoxically activating protective autophagy to shield
cancer cells from oxidative stress- induced cell apopto-
sis.180 Furthermore, some studies suggest that certain
immune cells, including macrophages, can produce high
levels of ROS and release them into the tumor microen-
vironment (TME), leading to an imbalance in cellular
redox homeostasis and inducing autophagy in cells.181,182
Tumor- associated macrophages (TAMs) derived from em-
bryonic origins, containing T cell immunoglobulin and
mucin domain containing 4, can promote peritoneal me-
tastasis of ovarian cancer by attenuating mTORC1 activa-
tion to enhance mitochondrial autophagy activity, thereby
alleviating oxidative stress.183 In BRCA- mutated ovarian
cancer cells, induction of ROS accumulation in stromal
cells leads to oxidative stress, resulting in the transforma-
tion of stromal phenotype, loss of Caveolin- 1 expression
in fibroblasts, and activation of NF- κB. Ultimately, this
activates autophagy and mitophagy in the tumor stroma,
leading to the acquisition of anti- apoptotic biological
characteristics in BRCA- mutated OCs.184
While accumulated ROS can induce autophagy,
activated autophagy can also regulate oxidative stress by
eliminating ROS.185 Literature reports indicate that in
ovarian cancer fibroblasts, autophagy mediated by ATG5
and Beclin- 1 can suppress ROS production to counteract
oxidative stress. Therefore, autophagy mediated by ATG5
and Beclin- 1 can inhibit the sensitivity of ovarian cancer
fibroblasts to platinum chemotherapy drugs.186
5.1.5
|
ROS serves as a convergence point for
various stress responses regulating autophagy,
highlighting the bidirectional regulatory
relationship between ROS and autophagy
In recent years, increasing evidence suggests that various
stress responses, including hypoxia, starvation, and en-
doplasmic reticulum stress, can regulate ROS to impact
oxidative stress. In the ovaries, hypoxia leads to ROS pro-
duction and consequent oxidative stress.187 In a cellular
pathological environment, insufficient nutrition in the
ER leads to abnormal protein folding processes. During
protein folding in the ER, abnormal disulfide bonds are
recognized by the body, leading to a reduction in the for-
mation of disulfide bonds by glutathione and a decrease
in the GSSH ratio. This process results in the accumula-
tion of misfolded proteins in the endoplasmic reticulum
lumen, activating the UPR response and promoting the
generation of ROS in the endoplasmic reticulum, leading
to the accumulation of ROS.128,188 When ROS accumulates
to an imbalance in the redox state within cells, antioxi-
dant mechanisms are compromised, leading to the activa-
tion of oxidative stress and autophagic responses. Under
starvation conditions, nutrient deprivation promotes the
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generation of ROS, especially H2O2, in mitochondria. H2O2
can oxidize ATG4, rendering it inactive, and the inactiva-
tion of ATG4 leads to lipidation of ATG8, promoting the
formation of autophagosomes.189–191 Although ROS plays
a crucial role in regulating autophagy, this regulatory rela-
tionship is not unidirectional. Mitophagy, for instance, se-
lectively eliminates damaged mitochondria, the primary
source of mtROS in oxidative stress, thereby restricting
the generation of mitochondrial ROS (Figure5).192,193
5.2
|
Natural products can modulate
autophagy influenced by cellular stress
conditions in cancer
In recent years, natural products have garnered atten-
tion due to their low cost, diverse biological effects, and
significant potential in cancer treatment. Numerous
studies have demonstrated the extensive regulatory role
of natural products in autophagy modulation, and the
activation of autophagy is controlled by cellular stress
responses. Here, we propose our viewpoint: Natural
products in cancer can activate cytotoxic autophagy by
promoting cellular stress responses, thus exerting anti-
cancer effects. 6- Shogaol enhances the antitumor effects
of 5- fluorouracil, oxaliplatin, and irinotecan in colon
cancer by promoting apoptosis and activating cytotoxic
autophagy (increased expression of LC3- II, Beclin- 1, and
Atg7) under hypoxic and glucose starvation conditions.194
Additionally, 6- Shogaol induces the expression of reac-
tive oxygen species and endoplasmic reticulum stress-
related proteins, thereby activating cytotoxic autophagy
(upregulation of LC3- II), leading to cell cycle arrest and
apoptosis in human liver cancer cells.195 According to
reports, ursolic acid triggered ER stress, subsequently
regulating apoptosis- and autophagy- related pathways
and increasing GEM chemosensitivity in pancreatic can-
cer cells by inhibiting the expression of RAGE.196 The
combination of Withaferin A and 5- FU induces the in-
creasing expression level of ER stress biomarkers like
BiP, PERK, CHOP, ATF- 4, and eIF2α. Cytotoxicity au-
tophagy and apoptosis mediated by ER stress lead to de-
creasing colorectal cancer cell viability.197 Additionally,
Withaferin A is closely associated with autophagy in
ovarian cancer. Combined treatment of Withaferin A
and doxorubicin can induce autophagic activity marked
by increased LC3B expression through ROS generation
in ovarian cancer, leading to significant reduction in cell
proliferation and microvessel formation. The combina-
tion of Withaferin A and doxorubicin allows for a reduc-
tion in the dosage of doxorubicin, thereby minimizing or
eliminating the severe side effects associated with high
doses of DOX.87 Zerumbone induces ER stress, proved
by the increased expression of GRP- 78 and CHOP/
GADD153. Subsequently, the activation of ER stress re-
sults in apoptosis and autophagy in hormone- refractory
prostate cancers.198 Knockdown STIM1 attenuated
DIM induced apoptosis and autophagy by inhibiting p-
AMPK mediated ER stress pathway in gastric cancer.199
Docosahexaenoic acid enhances oxaliplatin- induced
autophagy by promoting endoplasmic reticulum stress,
leading to decreased viability of colorectal cancer cells.200
Isoaaptamine promotes apoptosis and autophagy by pro-
moting the activation of LC3B, and p62 in breast cancer.
This process is mediated by oxidative stress.201 Three
pentacyclic triterpenoids (PTs), including glycyrrhetinic
acid (GA), ursolic acid (UA), and oleanolic acid (OA),
were used as raw materials into CDs to improve their
original poor water solubility. PTs- CDs induced selec-
tive killing by targeting tumor mitochondria for apopto-
sis, autophagy, and ferroptosis, respectively, due to high
sensitivity to ROS- induced damage and high internal
oxidative stress.202 Guttiferone K sensitizes cancer cells
to nutrient stress- induced cell death, with a significant
reliance on the process of autophagy.203 GGA provides
a substantial accumulation of autophagosomes when
FIGURE Under normal circumstances, autophagy is typically activated in cells under stress conditions, thereby maintaining the
survival of cancer cells. However, sometimes, continued and heightened stress leads to autophagy overactivated and causes cell damage,
leading to cell death. However, the regulation of autophagy by stress responses is not unidirectional; autophagy can also control cellular
stress responses by modulating ROS. In a word, they interact with each other, jointly regulating the survival and death of cancer cells.
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LI etal.
subjected to serum- starvation conditions through the
regulation of LC3B and P62 in human hepatoma cells.204
However, there is also evidence indicating that while
natural products exhibit anticancer effects in cancer ther-
apy, the activation of autophagy through stress response
can simultaneously exert a protective role, thereby inhib-
iting their efficacy. Combining natural products with au-
tophagy inhibitors can enhance their anticancer effects.
Docosahexaenoic acid monoglyceride (MAG- DHA) offers
superior bioavailability in comparison with other formu-
lations of docosahexaenoic acid. MAG- DHA triggers oxi-
dative stress- mediated ER stress, which can be proved by
activation of the PERK- eIF2α pathway in endoplasmic re-
ticulum. The induction of autophagy inhibits its capacity to
prompt apoptosis in breast cancer.205 The inhibitory effect
of flavokawain B on glioma growth triggers protective au-
tophagy and induces senescence within ER stress through
the ATF4- DDIT3- TRIB3- AKT–MTOR- RPS6KB1 signaling
pathway. The combination therapy of flavokawain B with
autophagy inhibitors may convert senescence into apop-
tosis, thereby enhancing the inhibitory effect of flavoka-
wain B on glioblastoma.206 In pancreatic cancer PANC- 1
cells treated with Fisetin, the expression of the transcrip-
tion factor p8 increases, and it regulates the expression of
ATF6, ATF4, and PERK through the p53/PKC- α pathway
in response to ER stress, ultimately leading to the activa-
tion of autophagy. Since Fisetin- induced autophagy has
a cytoprotective effect, co- treatment of 3- MA or CQ, au-
tophagy inhibitors, with Fisetin enhances the inhibitory
effect on proliferation of PANC- 1 cells.207 Under treat-
ment with Benzyl isothiocyanate, ER stress is activated,
leading to a cytosolic Ca2+ increase and PERK and eIF2-
phosphorylation. However, 4- PBA (the ER stress inhibi-
tor) suppresses autophagy, enhancing the inhibitory effect
of BITC on tumor growth and inhibiting lung cancer pro-
gression.208 Low concentrations of 3,3′- Diindolylmethane
have been shown to stimulate BRCA1 signaling and ex-
pression in breast cancer cells, thereby partially inhibiting
beclin1 and suppressing oxidative stress- induced cyto-
toxic autophagy mediated by H2O2, promoting cancer cell
survival (Figure6 and Table2).209
5.3
|
Natural products involved in
ovarian cancer therapy by modulating
autophagy through regulating stress
responses
In recent years, the ability of natural products to activate
stress- induced autophagy in cancer cells has been gradu-
ally elucidated. Here, we focus on natural compounds
that can regulate this biological process, inhibiting the
malignant progression of ovarian cancer cells. We hope to
provide more personalized choices and theoretical basis
for chemotherapy regimens for ovarian cancer (Figure7
and Table3).
5.3.1
|
Resveratrol
Resveratrol is a natural polyphenol abundant in peanuts,
pistachios, and grapes.230 Some in vitro studies suggest
that resveratrol- induced autophagy can promote cancer
cell survival and also can induce cancer cell death.231–233
Resveratrol can induce autophagy in gastric cancer cell
lines and may promote cell apoptosis due to sustained
endoplasmic reticulum stress.234 Resveratrol treatment
inhibits the expression of STIM1, triggering ER stress
through suppressing ER calcium storage and storing op-
erated calcium entry (SOCE). The decreased SOCE leads
to autophagy- mediated apoptosis in prostate cancer.235
Resveratrol also exhibits broad effects in ovarian can-
cer. Resveratrol triggers ER stress- mediated apoptosis by
disrupting N- linked glycosylation of proteins in ovarian
cancer cells.236 Resveratrol also enhances cytotoxic ef-
fects of cisplatin by inducing cell cycle arrest and apop-
tosis in SKOV- 3 cells through activating the p38 MAPK
and suppressing AKT.237 Resveratrol can mimic glucose
starvation conditions, activate autophagy to inhibit IL-
6- induced cell migration, and suppress ovarian tumor
growth in mouse models.218–220 Additionally, invitro evi-
dence suggests that resveratrol can inhibit ovarian cancer
cell metastasis by promoting autophagy and enhancing
BAX- mediated cell death, thereby increasing sensitivity
to platinum- based therapy.238 Therefore, we believe that
resveratrol holds the potential to offer more personalized
choices for ovarian cancer chemotherapy in the future.
5.3.2
|
Elaiophylin
Elaiophylin, a natural C2- symmetric macrodiolide an-
tibiotic isolated from Streptomyces melanosporus,221
has been demonstrated to be a novel autophagy inhibi-
tor with anticancer activity in various types of cancer.90
Elaiophylin suppressed mitophagy, induced oxidative
stress, and led to autophagic cell death in human uveal
melanoma via modulating SIRT1/FoxO3a signaling.222
Elaiophylin disrupts autophagic flux, interferes with the
degradation of unfolded proteins, consequently activating
fatal processes, and induces endoplasmic reticulum stress,
ultimately leading to apoptosis in multiple myeloma can-
cer cells.223 Elaiophylin induces excessive endoplasmic
reticulum stress in ovarian cancer cells and inhibits au-
tophagy by overactivating MAPK, thereby suppressing
resistance to platinum, taxanes, and PARP inhibitors.239
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This evidence demonstrates the significant potential of
Elaiophylin as an autophagy inhibitor in combating resist-
ance to current chemotherapy regimens.
5.3.3
|
Curcumin
Curcumin, extracted from the root of the turmeric plant,
is a significant component of traditional medicine in India
and China, known for its antioxidant, anti- inflammatory,
and anticancer properties.240 Curcumin suppresses the
Akt/mTOR/p70S6K pathway and triggers the ERK1/2
pathway, both of which control autophagy in response to
nutrient deprivation. The modulation of these two signal-
ing pathways results in the activation of autophagy and cell
death in malignant glioma cells.241 Curcumin has been re-
ported to inhibit cancer cell growth in ovarian cancer.242
The synthetic monocarbonyl analog of curcumin, (1E,
4E)- 1,5- bis(2- methoxyphenyl)penta- 1,4- dien- 3- one (re-
ferred to as B19), induces endoplasmic reticulum stress
and activates autophagy, leading to apoptosis in ovarian
cancer cells HO8910. However, specific autophagy in-
hibitor 3- MA, which suppresses autophagy, enhances
B19- induced endoplasmic reticulum stress and cell
apoptosis.224
5.3.4
|
Quercetin
Quercetin is a flavonoid compound found widely in
various plants and vegetables. It has been extensively
demonstrated to exert anticancer effects by promoting
apoptosis, inhibiting proliferation, metastasis, and angio-
genesis.243 Moreover, the anticancer effects of Quercetin
have been confirmed by a population- based study. The
results of the population survey indicate that dietary
intake of Quercetin can reduce the risk of gastric can-
cer.244 Quercetin has been shown to evoke endoplasmic
reticulum (ER) stress leading to cellular death in ovarian
cancer, leading to the involvement of the mitochondria
apoptosis pathway via the p- STAT3/Bcl- 2 axis. However,
during this process, the ER stress activated by Quercetin
can also simultaneously trigger protective autophagy.
Treatment of ovarian cancer cells with 3- MA (an au-
tophagy inhibitor) can enhance the anticancer effects of
Quercetin.74,225
FIGURE In cancer, natural products regulate autophagy by modulating intracellular stress responses. By Figdraw(ID: PYSPAc4444).
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TABLE Natural products that modulate autophagy mediated by regulating stress responses to control the malignant progression of cancer.
Drug Name
Drug
Classification Source
Activation on which
stress response The role of autophagy Affects autophagy molecules References
6- Shogaol Polyphenols Dried ginger Starvation, Hypoxia, ER
stress
Cytotoxic autophagy LCII/I, Beclin- 1, Atg7 expression
increased
[194,195,210,211]
Flavokawain B Flavonoids The traditional
Chinese
medicine
material Alpinia
pricei Hayata
ER stress Protective autophagy LC3B- II, ATG5 and ATG7
increased, P62 decreased
[206,212]
Fisetin Flavonoids Fruits and
vegetables
ER stress Protective autophagy LC3B increased [207,213]
Ursolic acid Terpenoids Fruits and
vegetables
ER stress Cytotoxic autophagy ATG5, LC3- II expression increased [196]
Withaferin A Lactones Ashwagandha ER stress Cytotoxic autophagy P62, LC3- II expression increased [197,214]
Benzyl isothiocyanate Isothiocyanates Broccoli and
cabbage
ER stress Protective autophagy LC3- II expression increased [208,215]
Zerumbone Terpenoids Zingiber
zerumbet Smith
ER stress Cytotoxic autophagy LC3- II expression increased [198,216]
3,3′- Diindolylmethane Alkaloids Cruciferous
vegetables
Oxidative stress, ER stress Low concentrations of DIM
inhibit cytotoxic autophagy;
high concentrations
promote cytotoxic
autophagy
The increase in LC3- II expression
was inhibited at low concentrations
of DIM; LC3- II expression increased
at high concentrations
[199,209]
Docosahexaenoic acid Organic acids Fatty fish
(salmon, tuna,
mackerel)
ER stress Promote cytotoxic
autophagy in colorectal
cancer; promote protective
autophagy in breast cancer
LC3 and P62 expression increased
in colorectal cancer; LC3BII and
Beclin- 1 expression increased, P62
decreased in breast cancer
[200,205,217]
Isoaaptamine Alkaloids Aaptos sp.
(marine
sponges)
Methanolic
extract
Oxidative stress Cytotoxic autophagy LC3II, P62 expression increased;
mTOR expression decreased
[201]
Pentacyclic triterpenoids Terpenoids Plants and fungi Oxidative stress Cytotoxic autophagy LC3B- II and mTOR expression
increased
[202]
Guttiferone K Polyphenols Garcinia cowa
Roxb.
Starvation Cytotoxic autophagy LC3- II expression increased, P62
expression decreased
[203]
Geranylgeranoic acid Terpenoids Multiple
medicinal herbs
Starvation Cytotoxic autophagy LC3II, P62 expression increased [204]
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5.3.5
|
Halofuginone
Halofuginone is a clinically active derivative of febrifug-
ine that was first isolated from the Chinese herb Dichroa
febrifuga. It is widely used in the treatment of parasitic
diseases, cancer, and autoimmune disorders.245 In vari-
ous cancers, halofuginone has been reported to inhibit
cancer cell migration and invasion, and to enhance the
sensitivity to platinum- based and 5- FU chemotherapy
drugs.246–248 Furthermore, halofuginone has been re-
ported to play a significant role in cellular nutrient me-
tabolism and autophagy regulation: In colorectal cancer,
halofuginone activates autophagy under nutrient- rich
conditions and inhibits autophagy under nutrient-
deprived conditions. Through its dual regulation of
autophagy, halofuginone slows tumor growth in mice
subjected to either standard or calorie- restricted diets.249
In ovarian cancer cells, OAW- 42, halofuginone- induced
amino acid starvation response is time- dependent
and associated with autophagy. Halofuginone mim-
ics the effect of proline starvation, triggering an amino
acid starvation response, inducing the formation of
autophagosomes, and slowing their fusion and degrada-
tion with lysosomes.228
5.3.6
|
Kaempferol
Kaempferol is widely present in various vegetables and
fruits, possessing powerful antioxidant properties. It plays
a beneficial role in reducing the risk of chronic diseases,
particularly cancer.250 Kaempferol promotes antioxidant
enzymes and inhibits ROS generation and lipid peroxida-
tion, ultimately preventing hemolysis and inhibiting the
growth of bladder cancer cell.251 Kaempferol has been re-
ported to attenuate oleic acid- induced lipid accumulation
and oxidative stress in the liver cancer cell line HepG2.252
In HeLa cells, Kaempferol inhibits glucose uptake and
Complex I of the mitochondrial respiratory chain, leading
to energy depletion. Autophagy is activated to counteract
apoptosis in response.253 Kaempferol plays a broad role
in inhibiting ovarian cancer progression. It induces cell
cycle arrest, inhibits proliferation, suppresses angiogen-
esis, and promotes apoptosis in ovarian cancer cells.254,255
FIGURE Natural products involved in ovarian cancer therapy by modulating autophagy through regulating stress responses. By
Figdraw(ID: YWSWRce48e).
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LI etal.
In ovarian cancer cells A2780 treated with Kaempferol,
an increase in intracellular calcium ions leads to endo-
plasmic reticulum stress response, subsequently activat-
ing autophagy, inducing cell apoptosis, and reducing cell
viability.226 Furthermore, there is evidence suggesting
that the combination of cisplatin with Kaempferol treat-
ment helps to inhibit drug resistance in ovarian cancer
cells.254
6
|
DISCUSSION AND PROSPECT
The reviewed literature demonstrates that autophagy
plays a dual role in cell survival and cell death during
tumor progression. In the early stages of tumorigenesis
and progression, autophagy typically acts as a tumor
suppressor and plays an anticancer role. However, re-
cent evidence suggests that in the late stages of tumor
development, autophagy plays a protective role by
providing sufficient nutrients to support the growth
of cancer cells through its own energy metabolism.
Therefore, autophagy plays a crucial role in determin-
ing the direction of ovarian cancer progression, acting
as a double- edged sword, and serving as a significant
therapeutic target for ovarian cancer. Numerous studies
have found that autophagy undergoes complex intracel-
lular self- regulation under stress conditions, including
the removal of damaged organelles, response to redox
imbalance in the tumor microenvironment, and stimu-
lation by chemotherapeutic drugs. Under normal cir-
cumstances, autophagy is typically activated in cells
under stress conditions, thereby maintaining the sur-
vival of cancer cells. However, sometimes, continued
and heightened stress leads to autophagy overactivated
and causes cell damage, leading to cell death. However,
the regulation of autophagy by stress responses is not
unidirectional; autophagy can also control cellular
stress responses by modulating ROS. In a word, they
interact with each other, jointly regulating the survival
and death of cancer cells.
The literature reviewed here reveals that these com-
pounds, derived from the bounty of nature, possess
the unique ability to modulate various forms of auto-
phagy. With these properties, they intricately regulate
the autophagic process, influencing initiation, vesicle
nucleation, vesicle elongation, vesicle fusion, and deg-
radation and recycling. Natural products can inhibit
the malignant progression of ovarian cancer, affect-
ing various malignant biological behaviors, including
proliferation, migration, invasion, angiogenesis, drug
resistance, autophagy, ROS production, cell cycle, and
apoptosis. Due to their widespread involvement in var-
ious stages of autophagy, natural products can exert
TABLE Natural products involved in ovarian cancer therapy by modulating autophagy through regulating stress responses.
Drug Name
Drug
Classification Source
Activation on which
stress response The role of autophagy Affects autophagy molecules References
Resveratrol Polyphenols Peanuts, pistachios, and grapes Starvation Cytotoxic autophagy LC3B II/I increased; Promote
autophagosome formation
[218–220]
Elaiophylin Lactones Streptomyces melanosporus ER stress Inhibiting autophagy to
suppress tumor growth
Increase in P62 [221–223]
B19 Polyphenols The synthetic monocarbonyl
analog of curcumin
ER stress Protective autophagy Autophagosome formation; increase in
LC3- II/LC3- I ratio
[224]
Quercetin Flavonoids Plants and vegetables ER stress Protective autophagy Increase in LC3B, Beclin 1, and Atg5
expression
[225]
Kaempferol Flavonoids A variety of plants ER stress Cytotoxic autophagy Increase in LC3B, Beclin 1, and Atg5
expression
[226,227]
Halofuginone Alkaloid Dichroa febrifuga Starvation Inducing autophagosome
formation, inhibiting their
fusion with lysosomes and
degradation
Increase in LC3B- II/I ratio [228,229]
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LI etal.
anticancer effects by modulating autophagy to control
multiple malignant biological behaviors of ovarian can-
cer. Furthermore, since autophagy is often activated in
response to cellular stress, natural products can pro-
mote excessive autophagy induced by the exacerbation
of cancer cellular stress response, leading to cell death.
Additionally, in the process of exerting anticancer ef-
fects, some drugs also activate protective autophagy
caused by stress responses, which in turn inhibits their
anticancer effects. Although some natural products may
activate protective autophagy, reducing their efficacy,
their combined use with autophagy inhibitors remains
a viable treatment option. Furthermore, some invivo
and in vitro studies have shown that, while achiev-
ing the same anticancer efficacy, the dosage of natu-
ral products can be equal to or even less than that of
first- line chemotherapy drugs.95,256 Additionally, natu-
ral products exhibit relatively low cytotoxicity, showing
significant anticancer effects without harming normal
healthy cells, which can greatly reduce the health bur-
den on ovarian cancer patients caused by chemother-
apy drugs.90,256 These findings indicate the immense
potential and natural advantages of using natural prod-
ucts as emerging anticancer agents for ovarian cancer
in the future. Moreover, natural products have proven
effective against various chemoresistant ovarian cancer
cell lines, and their combined use with chemotherapy
drugs has shown superior efficacy compared to single-
drug treatments.94,256,257 The use of natural products in
combination therapies can also reduce the dosage of
chemotherapy drugs while mitigating resistance and ef-
fectively reducing the side effects caused by high- dose
chemotherapy.87 These evidences suggest that natural
products can optimize current first- line ovarian cancer
treatments and provide more options for existing thera-
peutic strategies. However, the pharmacological actions
of natural products are highly complex. Different drug
concentrations can affect their roles in the autophagy
process and even within different types of cancers, the
efficacy of the same natural product varies. This com-
plexity might result in clinical trial outcomes for nat-
ural products in other cancers not being indicative for
ovarian cancer treatment, highlighting the importance
of conducting more clinical trials on natural products
for ovarian cancer treatment in the future. Ensuring the
stability of their efficacy amidst such complex pharma-
cological actions is a crucial issue that requires attention
moving forward. Moreover, due to the complex modula-
tory nature of cellular stress- induced autophagy, its im-
pact on the diverse pharmacological effects of natural
products remains incompletely elucidated. Therefore, it
is highly necessary to focus future research on elucidat-
ing the precise molecular mechanisms by which these
natural products influence the progression of ovarian
cancer. Such foundational studies will aid in interpret-
ing clinical trial results and assessing the efficacy, sta-
bility, and safety of natural products in the treatment of
ovarian cancer.
In summary, natural products, with their versatile and
intricate roles in regulating cellular stress and autophagy,
emerge as promising candidates for controlling cancer
progression. These findings further emphasize the impor-
tance of harnessing the power of nature in our ongoing
battle against malignancies. Through further research and
clinical applications, these gifts from nature are poised to
become integral components of future cancer treatment
strategies, offering improved therapeutic options and in-
creased chances of survival for patients.
AUTHOR CONTRIBUTIONS
Dongxiao Li and Min Wang conceptualized the research
topic. Dongxiao Li contributed to literature review.
Dongxiao Li and Danbo Geng participated in manuscript
writing and figure preparation and coordinated the study.
All authors have read and approved the final manuscript.
ACKNOWLEDGMENTS
We appreciate the assistance of ChatGPT in language
refinement.
FUNDING INFORMATION
This study was granted from the National Key Research
and Development Program (2018YFC1004203).
DISCLOSURES
The authors have no conflict of interest.
DATA AVAILABILITY STATEMENT
The original data in our study are available from the cor-
responding author on reasonable request.
ORCID
Dongxiao Li https://orcid.org/0009-0004-0600-507X
Danbo Geng https://orcid.org/0009-0002-6029-0604
Min Wang https://orcid.org/0000-0002-8269-4442
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How to cite this article: Li D, Geng D, Wang M.
Advances in natural products modulating
autophagy influenced by cellular stress conditions
and their anticancer roles in the treatment of
ovarian cancer. The FASEB Journal.
2024;38:e70075. doi:10.1096/fj.202401409R
