Atorvastatin Induces Mitochondria-Dependent Ferroptosis via the Modulation of Nrf2-xCT/GPx4 Axis

Zhang, Qi; Qu, Hang; Chen, Yinghui; Luo, Xuan; Chen, Chong; Xiao, Bing; Ding, Xiaowei; Zhao, Pei; Lu, Yao; Chen, Alex F.; Yu, Yanshan

doi:10.3389/fcell.2022.806081

Cited by 47 publications

(47 citation statements)

References 62 publications

(68 reference statements)

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“… 16 Ferroptosis has also been found to be involved in rhabdomyolysis caused by exertional heat stroke 27 and in atorvastatin-induced myopathy. 28 In our study, mRNA sequencing performed on skeletal muscles showed that the ferroptosis pathway was markedly enriched in COPD, accompanied by abnormal expression of Gpx4 and Ncoa4 . Our study further demonstrated a decrease in GPX4 and GSH, but an increase in 4-HNE and LPO in skeletal muscles from CS-induced COPD mice, which was consistent with the in vitro results observed in C2C12 myotubes stimulated by CSE, as demonstrated by an increase in cell death, Fe 2+ and lipid ROS.…”

Section: Discussionmentioning

confidence: 49%

Myostatin/HIF2α-Mediated Ferroptosis is Involved in Skeletal Muscle Dysfunction in Chronic Obstructive Pulmonary Disease

Zhang¹,

Li²,

Chang³

et al. 2022

COPD

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Objective Skeletal muscle dysfunction is an important comorbidity in patients with chronic obstructive pulmonary disease (COPD), and is associated with poor quality of life and reduced survival, but the mechanisms involved remain elusive. Ferroptosis is a newly discovered type of cell death resulting from iron‐dependent lipid peroxide accumulation. The purpose of this study was to examine whether ferroptosis is involved in COPD-associated skeletal muscle dysfunction. Methods A mouse model of COPD was established after 24 weeks of cigarette smoke (CS) exposure, and mRNA sequencing, hematoxylin-eosin (H&E) staining, immunostaining (IF), RT-PCR, and Western blot were utilized to identify the changes in gastrocnemius muscles. In vitro, C2C12 myotubes were treated with CS extract (CSE) and evaluated for ferroptosis-related molecules. The pathways regulating ferroptosis were then explored in CSE-stimulated myotubes. Results Compared with controls, COPD mice showed an enriched ferroptosis pathway. Gpx4 was decreased, while hypoxia-inducible factor (Hif) 2α was increased, at gene and protein levels. A reduced level of GSH, but increased cell death, Fe 2+ , lipid ROS, LPO, and 4-HNE were observed in COPD mice or in CSE-stimulated C2C12 myotubes, which could be ameliorated by ferroptosis inhibitors. The expression of myostatin (MSTN) was enhanced in COPD mice and CSE-stimulated myotubes. MSTN up-regulated HIF2α expression and led to ferroptosis in myotubes, whereas inhibition of MSTN binding to its receptor or inhibition/knockdown of HIF2α resulted in decreased cell death, and partially restored GPX4 and GSH. Conclusion CS exposure induced ferroptosis in vivo and in vitro. Mechanistically, CS-exposure upregulated MSTN which further induced ferroptosis through HIF2α in skeletal muscles, which may contribute to muscle dysfunction through impairing metabolic capacity and decreasing muscle fiber numbers, revealing a potential novel therapeutic target for COPD-related skeletal muscle dysfunction.

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Section: Discussionmentioning

confidence: 49%

Myostatin/HIF2α-Mediated Ferroptosis is Involved in Skeletal Muscle Dysfunction in Chronic Obstructive Pulmonary Disease

Zhang¹,

Li²,

Chang³

et al. 2022

COPD

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“…By treatment of atorvastatin, the levels of ROS, Fe 2+ , and MDA were increased, whereas the level of GSH was decreased. A recent study inducted that atorvastatin exposure causes excessive iron content, ROS production, and lipid peroxidation accumulation in muscular cells [ 35 ]. On the other hand, Simvastatin treatment reduced ROS production induced by cholesterol in the kidney cortical collecting duct cell line [ 36 ].…”

Section: Discussionmentioning

confidence: 99%

“…On the other hand, Simvastatin treatment reduced ROS production induced by cholesterol in the kidney cortical collecting duct cell line [ 36 ]. The discrepancy in metabolic characteristics may be related to individual statin types in different studies [ 35 , 37 , 38 ]. At the same time, Fer-1 could reverse the effects of atorvastatin on ROS production, Fe 2+ , MDA, and GSH, indicated that the excessive production of ROS might be important to occur ferroptosis in adipose tissue.…”

Section: Discussionmentioning

confidence: 99%

Statin-Induced Geranylgeranyl Pyrophosphate Depletion Promotes Ferroptosis-Related Senescence in Adipose Tissue

Shu

Zhang

et al. 2022

Nutrients

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Statin treatment is accepted to prevent adverse cardiovascular events. However, atorvastatin, an HMG-CoA reductase inhibitor, has been reported to exhibit distinct effects on senescent phenotypes. Whether atorvastatin can induce adipose tissue senescence and the mechanisms involved are unknown. The effects of atorvastatin-induced senescence were examined in mouse adipose tissue explants. Here, we showed that statin initiated higher levels of mRNA related to cellular senescence markers and senescence-associated secretory phenotype (SASP), as well as increased accumulation of the senescence-associated β-galactosidase (SA-β-gal) stain in adipose tissues. Furthermore, we found that the levels of reactive oxygen species (ROS), malondialdehyde (MDA), and Fe2+ were elevated in adipose tissues treated with atorvastatin, accompanied by a decrease in the expression of glutathione (GSH), and glutathione peroxidase 4 (GPX4), indicating an iron-dependent ferroptosis. Atorvastatin-induced was prevented by a selective ferroptosis inhibitor (Fer-1). Moreover, supplementation with geranylgeranyl pyrophosphate (GGPP), a metabolic intermediate, reversed atorvastatin-induced senescence, SASP, and lipid peroxidation in adipose tissue explants. Atorvastatin depleted GGPP production, but not Fer-1. Atorvastatin was able to induce ferroptosis in adipose tissue, which was due to increased ROS and an increase in cellular senescence. Moreover, this effect could be reversed by the supplement of GGPP. Taken together, our results suggest that the induction of ferroptosis contributed to statin-induced cell senescence in adipose tissue.

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“…Glutathione peroxidase 4 (GPX4) is a key inhibitor of ferroptosis, and its downregulation in response to therapy coincides with the occurrence of ferroptosis [ 58 , 59 ]. The reduced levels of xCT and GPX4 following treatment with Brusatol support the occurrence of ferroptotic cancer cell death [ 60 , 61 ], which was mitigated following treatment with a ferroptosis inhibitor, ferrostatin 1. As NRF2 plays an important role in mitigating lipid peroxidation [ 14 , 38 ], we hypothesized that ferroptosis was associated with an increase in lipid peroxidation following NRF2 inhibition.…”

Section: Discussionmentioning

confidence: 99%

Targeting NRF2 Sensitizes Esophageal Adenocarcinoma Cells to Cisplatin through Induction of Ferroptosis and Apoptosis

Ballout

Chen

et al. 2022

Antioxidants

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Esophageal adenocarcinoma (EAC), the predominant type of esophageal cancer in the United States, develops through Barrett’s esophagus (BE)-dysplasia-carcinoma cascade. Gastroesophageal reflux disease, where acidic bile salts refluxate into the esophagus, is the main risk factor for the development of BE and its progression to EAC. The NFE2-related factor 2 (NRF2) is the master cellular antioxidant regulator. We detected high NRF2 protein levels in the EAC cell lines and primary tissues. Knockdown of NRF2 significantly enhanced acidic bile salt-induced oxidative stress, DNA damage, and inhibited EAC cell growth. Brusatol, an NRF2 inhibitor, significantly inhibited NRF2 transcriptional activity and downregulated the NRF2 target genes. We discovered that in addition to inducing apoptosis, Brusatol alone or in combination with cisplatin (CDDP) induced significant lipid peroxidation and ferroptosis, as evidenced by reduced xCT and GPX4 expression, two known ferroptosis markers. The combination of Brusatol and CDDP significantly inhibited EAC tumor xenograft growth in vivo and confirmed the in vitro data showing ferroptosis as an important mechanism in the tumors treated with Brusatol or Brusatol and CDDP combination. Our data support the role of NRF2 in protecting against stress-induced apoptosis and ferroptosis in EACs. Targeting NRF2 in combination with platinum therapy can be an effective strategy for eliminating cancer cells in EAC.

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Atorvastatin Induces Mitochondria-Dependent Ferroptosis via the Modulation of Nrf2-xCT/GPx4 Axis

Cited by 47 publications

References 62 publications

Myostatin/HIF2α-Mediated Ferroptosis is Involved in Skeletal Muscle Dysfunction in Chronic Obstructive Pulmonary Disease

Myostatin/HIF2α-Mediated Ferroptosis is Involved in Skeletal Muscle Dysfunction in Chronic Obstructive Pulmonary Disease

Statin-Induced Geranylgeranyl Pyrophosphate Depletion Promotes Ferroptosis-Related Senescence in Adipose Tissue

Targeting NRF2 Sensitizes Esophageal Adenocarcinoma Cells to Cisplatin through Induction of Ferroptosis and Apoptosis

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