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Heme metabolism. Heme is degraded by heme oxygenase (HO), leading to the generation of biliverdin, carbon monoxide, and ferrous iron. Biliverdin is subsequently converted to bilirubin by biliverdin reductase. Under most conditions, biliverdin and bilirubin act as anti-oxidants by scavenging or neutralizing reactive oxygen species (ROS). Carbon monoxide, a gaseous product, mainly functions in signaling transduction, including the vasodilation of blood vessels, production of anti-inflammatory cytokines, upregulation of anti-apoptotic effectors, and thrombosis. Ferrous iron is the major pro-oxidant in all metabolites of heme. However, heme oxygenase-1 (HO-1) activation also increases ferritin expression, which can bind to ferrous iron and detoxify its pro-oxidant effect. The black arrows indicate that biliverdin metabolize into bilirubin. The dotted arrow indicates that carbon monoxide serves a regulator in vasodilatory, anti-inflammatory, anti-apoptotic, anti-thromobtic, and angiogenesis activities. The dotted arrow below iron indicates the iron increase will increase ferritin, which neutralizes the pro-oxidant effect of iron.
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Heme oxygenase (HO)-1 is known to metabolize heme into biliverdin/bilirubin, carbon monoxide, and ferrous iron, and it has been suggested to demonstrate cytoprotective effects against various stress-related conditions. HO-1 is commonly regarded as a survival molecule, exerting an important role in cancer progression and its inhibition is considered...
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Heme oxygenase-1 (HO-1) is an intracellular enzyme that catalyzes the oxidation of heme to generate ferrous iron, carbon monoxide (CO), and biliverdin, which is subsequently converted to bilirubin. These products have anti-inflammatory, anti-oxidant, anti-apoptotic, and anti-thrombotic properties. Although HO-1 is expressed at low levels in most ti...
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... Izoforma HO-1 znajduje się między innymi w wątrobie, sercu, trzustce, jelitach oraz nerkach, podczas gdy HO-2 zlokalizowana jest w jądrach, śledzionie, śródbłonku i nerkach [5]. W komórkach ssaków występuje także konstytutywna izoforma HO-3, która zazwyczaj nie wykazuje aktywności katalitycznej [8]. Najlepiej poznaną izoformą hemooksygenazy jest HO-1, która została szczegółowo przeanalizowana pod kątem jej reakcji na zmiany patologiczne. ...
Przedmiot badań. Praca poświęcona jest analizie literatury dotyczącej terapeutycznych zastosowań tlenku węgla. Tlenek węgla (CO), niegdyś uważany wyłącznie za toksyczny gaz, obecnie jest postrzegany jako cząsteczka o istotnym potencjale terapeutycznym. Endogenna produkcja CO w organizmie podkreśla jego naturalną rolę w procesach fizjologicznych i sygnalizacyjnych. Zróżnicowane właściwości biologiczne tlenku węgla stanowiły impuls do przeprowadzenia pierwszych badań mających na celu weryfikację jego potencjału terapeutycznego oraz zastosowanie tej cząsteczki w leczeniu różnorodnych schorzeń. Cel badań. Celem pracy jest przedstawienie aktualnego stanu wiedzy dotyczącego potencjalnych zastosowań terapeutycznych tlenku węgla, zarówno w postaci inhalacji, jak i przeglądowi nowoczesnych związków chemicznych, tzw. donorów CO. Materiał i metody. Analiza literatury opierała się na pracach naukowych z lat 2015–2025, dostępnych m.in. w bazach PubMed, PubChem, Google Scholar, Wiley Online Library oraz Web of Science. Zastosowane słowa kluczowe to: „tlenek węgla” (carbon monoxide), „cząsteczki uwalniające tlenek węgla” (carbon monoxide releasing molecules, CORMs), „donory CO” (CO donors), „terapeutyczne zastosowanie tlenku węgla” (therapeutic use of carbon monoxide), „organiczne CORMs” (organic CORMs), „wolne od metali CORMS” (metal-free CORMs). Wyniki. Dane przedstawione w publikacjach wskazują, że tlenek węgla charakteryzuje się zróżnicowanym zakresem właściwości terapeutycznych, w tym działaniem przeciwzapalnym, cytoprotekcyjnym, immunomodulacyjnym oraz antyproliferacyjnym. Pierwsze próby klinicznego zastosowania terapeutycznego tlenku węgla opierały się na kontrolowanych inhalacjach CO. Jednakże metoda ta stanowi istotne wyzwanie w praktyce klinicznej, szczególnie pod względem doboru odpowiedniej dawki oraz braku korelacji między stężeniem karboksyhemoglobiny (COHb) we krwi a efektem terapeutycznym. Dodatkowo, badania przeprowadzone na modelach zwierzęcych sugerują, że skuteczność terapeutyczna tlenku węgla może być bardziej związana z jego miejscowym stężeniem w tkankach docelowych niż ze stężeniem COHb w krążeniu systemowym. Alternatywnym podejściem do podawania tlenku węgla metodą wziewną jest zastosowanie tzw. donorów CO, czyli proleków uwalniających tlenek węgla pod wpływem różnych czynników, takich jak wartość pH, temperatura, enzymy lub światło. W pracach eksperymentalnych dowiedziono, że to podejście cechuje się wysoką skutecznością farmakologiczną i wyższym profilem bezpieczeństwa. Szczególnie obiecujące wyniki uzyskano w przypadku podawania donorów tlenku węgla drogą doustną w zwierzęcych modelach schorzeń gastroenterologicznych, gdzie donory CO potwierdziły właściwości cytoprotekcyjne oraz przeciwzapalne. Wnioski. Pomimo obiecujących wyników w pracach eksperymentalnych, konieczne są dalsze badania nad optymalizacją właściwości lekopodobnych oraz parametrów farmakokinetycznych donorów tlenku węgla, aby w pełni wykorzystać potencjał terapeutyczny CO. Umożliwi to przeprowadzenie badań przedklinicznych i stworzy potencjalne możliwości zastosowania klinicznego. W szczególności dalsze badania nad doustnymi donorami CO mogą stanowić istotny krok w kierunku opracowania skutecznych i bezpiecznych terapii.
... It plays a vital role in cellular defense under stress conditions. Recent research suggests that elevated HO-1 levels can regulate ferroptosis, linking it to iron-induced cell death pathways [42]. HO-1 is also crucial for iron homeostasis and is a downstream target of the stress-responsive protein Nrf2, known for its anti-inflammatory and antioxidant properties [43,44]. ...
Recent studies have identified novel cardiac glycosides from natural sources with potential anti-tumor properties. Toxicarioside H (ToxH) is a novel cardiac glycoside isolated by our collaborative research team. However, its ability to induce ferroptosis in triple-negative breast cancer (TNBC) cells has not been investigated. Therefore, this study evaluates whether ToxH has the capability of inducing ferroptosis and elucidates the underlying molecular mechanisms. Treatment with ToxH led to dose- and time-dependent growth inhibition in BT-549 and MDA-MB-468 cells. Flow cytometry analysis and lactate dehydrogenase assay revealed that ToxH induced various forms of cell death in both BT-549 and MDA-MB-468 cells. Examination through transmission electron microscopy, along with flow cytometry analysis of 7-AAD-stained dead cells and ferroptosis markers BODIPY-C11 and Fe2+ ions, identified various forms of cell death induced by ToxH, including apoptosis, autophagy, apoptotic necrosis, and ferroptosis. Co-treatment with the ferroptosis inhibitor Fer-1 significantly reduced ToxH-induced cell death, indicating that ToxH primarily inhibits TNBC cell growth by inducing ferroptosis. Further investigation into the molecular mechanisms revealed upregulation of Nrf2 and HO-1 expression by ToxH. Effective inhibition of ToxH-induced ferroptosis was achieved through shRNA-mediated knockdown of HO-1 expression. Animal experiments demonstrated that ToxH treatment markedly suppressed tumor growth compared to the control group, while co-administration of Fer-1 led to an increase in tumor growth. These findings suggest that ToxH suppresses TNBC cell growth by modulating the Nrf2/HO-1 signaling pathway to induce ferroptosis. ToxH presents itself as a promising cardiac glycoside compound for TNBC treatment, warranting further translational research.
... Typically, the NRF2/HO-1 signaling pathway functions to suppress ferroptosis [94]. However, under specific circumstances, HO-1 can also contribute to pathological alterations [95]. Knockdown of centromere protein F (CENPF) shows less activity of NRF2 contributing to the decreased expression of the downstream antioxidant gene HO-1 for a compromised cellular steady state of antioxidants [96]. ...
Cervical cancer (CC) is a prevalent malignant tumor in the female reproductive system, with rising incidence rates among younger women posing a significant public health challenge. Human papillomavirus (HPV) infection is the primary cause, driving carcinogenesis by promoting abnormal proliferation of tumor cells. Ferroptosis is a form of regulated necrosis that is caused by an iron-dependent accumulation of lipid peroxides with rupture of the plasma membrane. Targeting ferroptosis-related molecules and pathways can selectively induce cervical cancer cell death, while alterations in the expression of ferroptosis-related genes provide promising biomarkers for prognostic assessment. Advances in research on biomarkers and molecular targets are improving predictions of therapeutic outcomes, overcoming drug resistance, and optimizing immunotherapy strategies, thereby opening new avenues for precision medicine. This review focuses on the molecular mechanisms underlying ferroptosis in cervical cancer, discusses its potential applications in early diagnosis and prognosis evaluation, and summarizes the latest advancements in targeted therapy, aiming to provide a novel perspective for the clinical management of cervical cancer.
... Studies have shown that the arsenic compound KML001 can promote the expression of the autophagy-specific protein LC3 through ROS, thus inducing autophagic cell death in PCa cells [132]. Ferroptosis is a unique form of programmed cell death, characterized by the high expression of HO-1 [133]. Excessive antioxidant HO-1 may directly interact with ROS in the presence of metal ions, such as copper and iron, ultimately leading to cell death through the ferroptosis pathway [134]. ...
Prostate cancer is the second most common malignancy among men worldwide, with its incidence and mortality rates steadily increasing. Although androgen deprivation therapy (ADT) combined with androgen receptor inhibitors has shown significant efficacy in treating prostate cancer, resistance to treatment remains a major challenge, particularly in patients with metastatic prostate cancer. Reactive oxygen species (ROS), a class of highly reactive molecules, can induce oxidative stress within cells, thereby affecting cellular survival and function. In cancer cells, elevated ROS levels not only promote proliferation and invasion but also contribute to the malignancy of tumors by modulating the tumor microenvironment, enhancing angiogenesis, and facilitating extracellular matrix remodeling. This review systematically explores the pathways of ROS generation in prostate cancer, their interaction with the androgen receptor signaling pathway, and the role of external factors such as obesity and aging in promoting ROS production. The findings highlight that ROS drive prostate cancer progression through multiple mechanisms, including altering the tumor microenvironment, activating the unfolded protein response (UPR), and regulating miRNA expression. By providing a comprehensive analysis of ROS-mediated mechanisms in prostate cancer, this review offers new insights into the development of targeted antioxidant therapeutic strategies.
... HO-1 is an enzyme that catalyzes the breakdown of heme into biliverdin, carbon monoxide (CO), and iron. Biliverdin is subsequently converted into bilirubin, which possesses potent antioxidant properties [8,10,11]. ...
... Highly-induced HMOX1 can facilitate the breakdown of heme to produce a large amount of free iron, which can further enhance the production of ROS and promote LPO. Therefore, HMOX1 can dually regulate iron and ROS homeostasis, and exert a major effect on ferroptosis [19,27]. Furthermore, HMOX1 has been reported in association with the inactivation of multiple signaling pathways such as AKT/GSK3β and WNT/β-catenin signaling pathways [28]. ...
The small-molecule targeting drug Surufatinib is a new strategy for pancreatic neuroendocrine neoplasms (pNENs). However, the adverse reactions of Surufatinib should not be ignored in clinical practice. Based on PROTAC technology, we developed a novel tyrosine kinase (TK) degrader PROTAC-Surufatinib (hereinafter referred to as P-Surufatinib). This study was designed to investigate the effects and underlying mechanism of P-Surufatinib on pNENs. In vitro, we revealed that P-Surufatinib could more effectively inhibit proliferation and angiogenesis, and degrade target proteins in pNENs cells than Surufatinib. The transcriptome sequencing revealed that HMOX1 was the key molecule of P-Surufatinib to inhibit proliferation in pNENs. It was demonstrated that HMOX1 was lowly expressed in pNENs, and P-Surufatinib could up-regulate the expression of HMOX1 in pNENs. Mechanistically, P-Surufatinib inhibited pNENs progression by inducing ferroptosis through the suppression of HMOX1 mediated WNT/β-catenin signaling pathway. In vivo, P-Surufatinib could obviously suppress the growth of subcutaneous tumors in nude mice and enhance the expressional level of HMOX1 in tumorous tissue. In summary, our findings reveal that P-Surufatinib can suppress pNENs progression via inducing ferroptosis through up-regulating the expressional level of HMOX1 by inhibiting WNT/β-catenin signaling pathway, which provides a novel treatment method for pNENs.
... In this regard, keeping in mind that cell metabolism is a crucial process to sustain cell growth and self-renewal, it leads to the fact that metabolic activities and the metabolites produced in the tumor could have an influence on ferroptosis (Jiang et al., 2024). Interestingly, Ocoxin caused an overexpression of HMOX1, a critical mediator in ferroptosis that promotes cell death in the presence of oxidative stress and high iron concentrations inside the cells (Chiang et al., 2018). Moreover, the nutritional supplement also deregulated the expression of NQO1, a gene responsible for redox control that is also involved in ferroptosis (Zhang, L. et al., 2018;Wang W. et al., 2023). ...
Cancer is one of the leading causes of death worldwide. Many therapies are being used to treat this disease, however, new treatments are now being implemented, since they are not always effective and their secondary effects represent one of the main reasons for cancer patients’ loss of life quality during the progression of the disease. In this scenario, Ocoxin is a mixture of plant extracts, amino acids, vitamins and minerals, known for its antioxidant, anti-inflammatory and immunoregulatory properties, which has shown to exert antitumor effects in many cancers. The aim of this study is to elucidate the mechanism of action of the compound in colorectal cancer, triple negative breast cancer, pancreatic cancer and prostate cancer. Analyses performed through RNA sequencing revealed that the main effect of Ocoxin appears to be the alteration of cell metabolism, especially inducing the process of ferroptosis. Nevertheless, the modulation of the cell cycle was also remarkable. Ocoxin altered 13 genes in common in all the four cancers that were not only associated to metabolism and cell cycle but were also involved in the integrated stress response and unfolded protein response, suggesting that the compound causes the induction of cell death through several pathways. Although the mechanisms vary according to the type of cancer, this study highlights the potential of Ocoxin as an adjunctive treatment to improve outcomes in cancer therapy.
... Moreover, an analysis of the GEPIA database indicated the significantly lower expression of HMOX1 in OC tissues compared with normal tissues ( Figure S3G). Studies have demonstrated that elevated HMOX1 levels are associated with ferroptosis induction, as observed with erastin [42,43]. Additionally, there is a possibility that there is an increased expression of the HMOX1 gene in OC cells treated with olaparib-Ga, which may be attributed to the heightened sensitivity to Fe 2+ -induced ROS [44]. ...
Ovarian cancer (OC) is a highly aggressive malignancy with a poor prognosis, necessitating novel therapeutic strategies. Fucoxanthin (FX), a marine-derived carotenoid from Laminaria japonica, has demonstrated promising anticancer potential. This study revealed that FX exerts multiple anticancer effects in OC by inhibiting cell proliferation, invasion, and migration, while inducing various forms of programmed cell death (PCD). FX triggered PANoptosis (apoptosis, necroptosis, and pyroptosis) and ferroptosis. FX treatment regulated key markers associated with PANoptosis, including apoptosis (Bcl-2, cleaved caspase-3), pyroptosis (GSDME), and necroptosis (RIPK3). Additionally, FX treatment modulated ferroptosis-related markers, such as SLC7A11 and GPX4, while increasing reactive oxygen species (ROS) and Fe²⁺ levels and disrupting mitochondrial function. Proteomic and molecular docking analyses identified AMP-activated protein kinase (AMPK) as a direct FX target, activating the AMPK/Nrf2/HMOX1 pathway to promote ferroptosis. In vivo, FX significantly reduced tumor growth in OC xenograft models, accompanied by enhanced ferroptosis marker expression. These findings demonstrate that FX induces ferroptosis through the AMPK/Nrf2/HMOX1 pathway and promotes PANoptosis via distinct mechanisms, highlighting its potential as a marine-derived therapeutic agent for OC.
... It is known that the increase in oxidative stress is an essential factor in tumor proliferation and invasion. However, at the same time, an excessive level of ROS can damage and lead to the death of tumor cells 38 . Both immunofluorescence and cytometric analysis showed a decrease in the amount of ROS in ACHN and Caki-1 cells grown in low [Na + ] compared to control (153 mM). ...
Hyponatremia is the most common electrolyte disorder in cancer patients and is associated with a worse outcome. This finding has also been reported in patients with metastatic renal cell carcinoma (mRCC). We have previously demonstrated that low extracellular sodium concentrations ([Na⁺]) increase cell proliferation and invasion in several human cancer cell lines. The aim of the present study was to evaluate in vitro the effects of mild [Na⁺] alterations on two mRCC cell lines, ACHN and Caki-1. After growth in reduced extracellular [Na⁺], we observed that even mild reductions of [Na⁺] significantly enhanced different key cancer cell features, including proliferation, invasion and migration. Furthermore, we observed a reduction in reactive oxygen species (ROS) levels in low [Na⁺], with a significant increase of the antioxidant Nrf2/HMOX-1 pathway. Since an excess of ROS causes cell death, this finding clarifies the role of Nrf2/HMOX-1 in maintaining the balance between oxidant and antioxidant species in the tumor environment, promoting cell survival. Although further clinical studies are needed, aiming for instance to determine whether serum [Na⁺] correction improves the outcome of patients with mRCC, our findings suggest that attention should be deserved to serum [Na⁺] in this setting.
... Similar results have been reported in studies of acute myeloid leukemia cells, human lung cancer cells, CRC cells and human breast cancer cells [77], [137], [138], [139], [140]. These data showed that high expression of HO-1 positively regulated ferroptosis through the modulation of iron and ROS levels, making it an important target for mediating the adverse effects of ferroptosis induction [141]. However, a previous study revealed that reduced HO-1 levels mediated synergistic lysosomotropic agent-and tyrosine kinase inhibitor-induced ferroptosis in glioblastoma cells [142]. ...
Ferroptosis is an iron-dependent nonapoptotic regulated cell death modality characterized by lethal levels of lipid peroxide accumulation and disrupted antioxidant systems. An increasing number of studies have revealed correlations between ferroptosis and the pathophysiology and treatment of cancer. Given the intricate involvement of mitochondria in ferroptosis, as suggested by previous studies, here, we review advances in understanding the roles of mitochondrial quality control and mitochondrial metabolism (including the roles of the TCA cycle, reactive oxygen species, iron metabolism, and lipid metabolism) in cancer-related ferroptosis and outline the molecular mechanism and clinical translation of mitochondria-related ferroptosis in cancer treatment. with the aim of promoting the precise utilization and prevention of ferroptosis in cancer therapeutics.
