Xinxin Ci’s research while affiliated with Jilin University and other places

Background Cisplatin is a widely used drug for the treatment of solid organ cancer, but its renal toxicity cannot be ignored. Amentoflavone (AME), a natural flavonoid compound, has remarkable pharmacological effects, including anti-inflammatory and antioxidative effects. The effect and mechanism of AME on cisplatin-induced acute kidney injury (CI-AKI) remain unclear. Methods We investigated the effect of AME on CI-AKI using the HK-2 cell line and C57BL/6 mice. Renal function, tissue damage, and molecular markers were assessed to explore the effects of AME on oxidative stress and cell death pathways. Results In vitro, AME significantly suppressed the cytotoxic effects of cisplatin on HK-2 cells. Furthermore, AME significantly inhibited cisplatin-induced ferroptosis and PANoptosis (apoptosis, pyroptosis and necroptosis). In mice with acute kidney injury induced by a single intraperitoneal injection of cisplatin, the daily administration of AME during AKI effectively improved renal function and alleviated renal tubular injury, characterized by the normalization of blood urea nitrogen (BUN) and serum creatinine (SCr) levels; it also inhibited cisplatin-induced renal ferroptosis and PANoptosis. AME is a natural antioxidant that activates the Nrf2 antioxidant pathway both in vivo and in vitro. In Nrf2 knockout mice and knockdown cells, the protective effect of AME against cisplatin-induced nephrotoxicity disappeared. However, after Nrf2 knockout, the effect of AME on ferroptosis completely disappeared, and that on PANoptosis partially disappeared. Conclusion Amentoflavone has a protective effect on cisplatin-induced acute kidney injury via a mechanism related to the Nrf2-dependent antioxidant pathway and the regulation of ferroptosis and PANoptosis.

Nrf1 is a transcription factor that is highly conserved and reacts to oxidative, proteotoxic and endoplasmic reticulum stress in cells; nonetheless, its function in the context of acute kidney injury (AKI) remains unclear. Using a model of cisplatin-induced nephrotoxicity in vitro and in vivo, we found that the expression of Nrf1, which is expressed at high levels in renal tubular cells, was significantly downregulated after cisplatin treatment. Proximal tubule-specific Nrf1 knockout worsened and Nrf1 overexpression attenuated cisplatin-induced (CI)-AKI. RNA sequencing analysis revealed that Nrf1 overexpression decreased the number of transcripts involved in cell death, specifically those associated with ferroptosis, after cisplatin treatment. Furthermore, ferroptosis responses, characterized by increased lipid peroxidation and iron content and decreased FPN, XCT and glutathione peroxidase 4 levels, were attenuated in Nrf1-overexpressing HK-2 cells but worsened in Nrf1-knockout mice and Nrf1-knockdown HK-2 cells. Moreover, lipidomic and RNA sequencing results indicated that Nrf1 regulated the levels of polyunsaturated fatty acids (PUFAs) and inhibited the expression of ACSL4. Additionally, ChIP experiments revealed that Nrf1 bound to the promoter region of ACSL4, thereby inhibiting its transcription. Furthermore, inhibitors of ACSL4 significantly reduced the sensitivity of HK-2 cells to ferroptosis induced by Nrf1 knockdown. Collectively, these findings suggest that Nrf1 is a novel target for inhibiting ferroptosis in renal tubule cells by suppressing the transcription and expression of ACSL4, thereby reducing PUFA levels. Consequently, activators developed for Nrf1 may hold therapeutic potential in the treatment of patients with CI-AKI.

Background Pyroptosis is an inflammatory form of regulated necrosis that has been implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD). However, the role of lipid peroxidation in pyroptosis and its underlying mechanisms in COPD remain unclear. Methods In vitro, human bronchial epithelial cells (Beas-2b cells) were exposed to cigarette smoke extract (CSE) for 24 h. In vivo, mice were exposed to cigarette smoke (CS) for 4 weeks. To investigate the role of xCT, we used siRNA and AAV6 to conditionally knock down xCT in vitro and in vivo, respectively. Results The administration of ferrostatin-1 (Fer-1), a ferroptosis inhibitor that inhibits lipid peroxidation, significantly reduced the cytotoxicity of CSE to Beas-2b cells and mitigated inflammatory exudation, lung injury and mucus hypersecretion in mice with CS-induced COPD. Fer-1 suppressed gasdermin D (GSDMD)-mediated pyroptosis caused by CS in vitro and in vivo. However, in Beas-2b cells and the lung epithelial cells of mice, conditional knockdown of xCT (a negative regulatory factor of lipid peroxidation) inhibited the xCT/GPx4 axis, leading to more severe lipid peroxidation and GSDMD-mediated pyroptosis during cigarette smoke exposure. Moreover, we found that CS promoted the degradation of xCT through the ubiquitin proteasome system (UPS) and that treatment with MG132 significantly inhibited the degradation of xCT and downregulated the expression of pyroptosis-related proteins. Conclusion The results of this study suggested that the ubiquitination-mediated degradation of xCT drives GSDMD-mediated pyroptosis in COPD and is a potential therapeutic target for COPD.

Background and Purpose: Mitochondrial dysfunction is essential in renal tubular damage, and mitophagy, a selective form of autophagy, specifically eliminates damaged mitochondria. Mitophagy reportedly protects against diabetic kidney disease, cisplatin-induced acute kidney injury (AKI) and other related kidney diseases, but the specific mechanism by which mitophagy protects against cisplatin-induced chronic kidney disease (CKD) remains unclear. Experimental Approach: The effects of farrerol on cisplatin-induced AKI in mice were investigated. C57BL/6 wild-type and Nrf2 knockout mice were used to evaluate the protective effect of farrerol on cisplatin-induced CKD. Key Results: we confirmed that Nrf2- and PINK1/Parkin-mediated mitophagy was significantly increased on the 3rd day of cisplatin stimulation but was reduced on the 38th day of cisplatin stimulation. Similar to previous results, farrerol, a natural compound, also activated Nrf2 on the 38th day of cisplatin administration, subsequently stimulating the Nrf2-targeted antioxidant enzymes HO-1 and NQO1. In addition, farrerol triggered PINK1/Parkin-mediated mitophagy by recruiting the receptor proteins LC3 and p62/SQSTM1, thereby eliminating damaged mitochondria. Furthermore, genetic deletion of Nrf2 reduced PINK1/Parkin-mediated mitophagy activation and led to increased renal tubular necrosis and renal fibrosis. We also found that farrerol alleviated inflammation and renal fibrosis by inhibiting p-NF-κB/NLRP3 and TGF-β/Smad signaling. Conclusions: These data indicated that farrerol effectively inhibited cisplatin-induced inflammation and renal fibrosis by activating Nrf2 and PINK1/Parkin-mediated mitophagy, which provides a potential novel therapeutic target for CKD.