Mitophagy alleviates cisplatin-induced renal tubular epithelial cell ferroptosis through ROS/HO-1/GPX4 axis

Lin, Qisheng; Li, Shu; Jin, Haijiao; Cai, Hong; Zhu, Xuying; Yang, Yuanting; Wu, Jinlong; Chen, Qi; Shao, Xinghua; Li, Jialin; Zhang, Kaiqi; Zhou, Wenyan; Zhang, Minfang; Cheng, Jiayi; Gu, Leyi; Mou, Shan; Ni, Zhaohui

doi:10.7150/ijbs.80775

Cited by 84 publications

(28 citation statements)

References 68 publications

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“…At the beginning of this experiment, we treated KGN cells with gradient concentrations of cisplatin to establish injured models. Cisplatin has been authenticated to induce the occurrence of ferroptosis in some cancer cells [ 42 ] and renal tubular epithelial cells [ 43 , 44 ]. We first proved cisplatin can induce ferroptosis in KGN cells in a dose-dependent manner by detecting the protein expression levels of ferroptosis-related molecules such as GPX4, Nrf2, FTH1 and SLC7A11.…”

Section: Discussionmentioning

confidence: 99%

Endometrial stem cells alleviate cisplatin-induced ferroptosis of granulosa cells by regulating Nrf2 expression

Pan,

Wang,

Cheng

et al. 2024

Reprod Biol Endocrinol

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Background Premature ovarian failure (POF) caused by cisplatin is a severe and intractable sequela for young women with cancer who received chemotherapy. Cisplatin causes the dysfunction of granulosa cells and mainly leads to but is not limited to its apoptosis and autophagy. Ferroptosis has been also reported to participate, while little is known about it. Our previous experiment has demonstrated that endometrial stem cells (EnSCs) can repair cisplatin-injured granulosa cells. However, it is still unclear whether EnSCs can play a repair role by acting on ferroptosis. Methods Western blotting and quantitative reverse-transcription polymerase chain reaction (qRT-PCR) were applied to detect the expression levels of ferroptosis-related genes. CCK-8 and 5-Ethynyl-2’-deoxyuridine (EdU) assays were used to evaluate cell viability. Transmission electron microscopy (TEM) was performed to detect ferroptosis in morphology. And the extent of ferroptosis was assessed by ROS, GPx, GSSG and MDA indicators. In vivo, ovarian morphology was presented by HE staining and the protein expression in ovarian tissue was detected by immunohistochemistry. Results Our results showed that ferroptosis could occur in cisplatin-injured granulosa cells. Ferroptosis inhibitor ferrostatin-1 (Fer-1) and EnSCs partly restored cell viability and mitigated the damage of cisplatin to granulosa cells by inhibiting ferroptosis. Moreover, the repair potential of EnSCs can be markedly blocked by ML385. Conclusion Our study demonstrated that cisplatin could induce ferroptosis in granulosa cells, while EnSCs could inhibit ferroptosis and thus exert repair effects on the cisplatin-induced injury model both in vivo and in vitro. Meanwhile, Nrf2 was validated to participate in this regulatory process and played an essential role.

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Section: Discussionmentioning

confidence: 99%

Endometrial stem cells alleviate cisplatin-induced ferroptosis of granulosa cells by regulating Nrf2 expression

Pan,

Wang,

Cheng

et al. 2024

Reprod Biol Endocrinol

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“…The mechanism of ER-phagy is slightly different from mitophagy in AKI. Mitophagy is irritability elevated in AKI, which indicates the protective role for eliminating mitochondrion after injury [ 13 – 15 , 36 ]. Nevertheless, in the present study, we show ER-phagy is reduced in contrast to IRI, cisplatin, and folic acid-induced AKI, and meanwhile, ER stress and apoptosis are aggravated, which suggests that IRI or drugs might directly work on ER and reduce ER-phagy, resulting downstream accumulation of ER stress and renal tubular epithelial cell death in AKI.…”

Section: Discussionmentioning

confidence: 99%

“…Cisplatin mice were treated as outlined in our previous work [ 15 ]. Mice were administered cisplatin (Jiangsu Hansoh, H20040813, 20 mg/kg body weight) via intraperitoneal injection.…”

Section: Methodsmentioning

confidence: 99%

DDRGK1-mediated ER-phagy attenuates acute kidney injury through ER-stress and apoptosis

Jin,

Yang,

Zhu

et al. 2024

Cell Death Dis

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Acute kidney injury (AKI) constitutes a prevalent clinical syndrome characterized by elevated morbidity and mortality rates, emerging as a significant public health issue. This study investigates the interplay between endoplasmic reticulum (ER) stress, unfolded protein response (UPR), and ER-associated degradation (ER-phagy) in the pathogenesis of AKI. We employed four distinct murine models of AKI—induced by contrast media, ischemia–reperfusion injury, cisplatin, and folic acid—to elucidate the relationship between ER-phagy, ER stress, and apoptosis. Our findings reveal a marked decrease in ER-phagy coinciding with an accumulation of damaged ER, elevated ER stress, and increased apoptosis across all AKI models. Importantly, overexpression of DDRGK1 in HK-2 cells enhanced ER-phagy levels, ameliorating contrast-induced ER stress and apoptosis. These findings unveil a novel protective mechanism in AKI, wherein DDRGK1–UFL1-mediated ER-phagy mitigates ER stress and apoptosis in renal tubular epithelial cells. Our results thereby contribute to understanding the molecular underpinnings of AKI and offer potential therapeutic targets for its treatment.

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“…Its protective role is attributed to the production of biliverdin and its toxic effects are due to excessive accumulation of Fe 2+ . However, a growing number of studies have shown that hyperactivation of HMOX1 increases cytotoxicity [22][23][24].…”

Section: Introductionmentioning

confidence: 99%

RNF181 promotes ferroptosis by ubiquitinating HMOX1 to inhibit gastric cancer cell proliferation and chemoresistance

Cui,

Zhou,

Chen

et al. 2024

Preprint

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Emergence of chemotherapeutic resistance remains an important challenge in cancer treatment, especially in advanced cancers. Recent studies have shown that ferroptosis is closely associated with tumor chemoresistance, and induction of ferroptosis has been shown to reverse chemoresistance. This study focused on the important function of Ring Finger Protein 181 (RNF181) in gastric cancer and the potential mechanisms involved in chemoresistance. Here, we found that RNF181 was aberrantly activated in chemoresistant cells of gastric cancer, and high expression of RNF181 was associated with poor patient prognosis. Depletion of RNF181 inhibited the proliferation and tumorigenicity of chemoresistant cells, and increased chemotherapeutic drug sensitivity. Mechanistically, our study showed that the interaction between RNF181 and HMOX1 mediated K27-linked polyubiquitination of HMOX1 and regulated its protein stability. Upregulation of HMOX1 expression after knockdown of RNF181 resulted in excessive heme degradation and intracellular iron overload to promote ferroptosis. Generally, our study reveals the important role of RNF181 in chemoresistance in gastric cancer, and targeting RNF181 may be a rational strategy to improve the efficacy of chemotherapy in gastric cancer.

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Mitophagy alleviates cisplatin-induced renal tubular epithelial cell ferroptosis through ROS/HO-1/GPX4 axis

Cited by 84 publications

References 68 publications

Endometrial stem cells alleviate cisplatin-induced ferroptosis of granulosa cells by regulating Nrf2 expression

Endometrial stem cells alleviate cisplatin-induced ferroptosis of granulosa cells by regulating Nrf2 expression

DDRGK1-mediated ER-phagy attenuates acute kidney injury through ER-stress and apoptosis

RNF181 promotes ferroptosis by ubiquitinating HMOX1 to inhibit gastric cancer cell proliferation and chemoresistance

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