Inhibiting xCT/SLC7A11 induces ferroptosis of myofibroblastic hepatic stellate cells but exacerbates chronic liver injury

Du, Kuo; Oh, Seh Hoon; Dutta, Rajesh Kumar; Sun, Tianai; Yang, Wen‐Hsuan; Ashley, Jen-Tsan

doi:10.1111/liv.14945

Cited by 34 publications

(27 citation statements)

References 45 publications

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“…Likewise, SLC7A11 and GPX4 were expressed in mouse primary HSCs. 13 , 37 More importantly, it has been found that inhibitions of SLC7A11 and GPX4 are involved in cell ferroptosis. 9 , 38 Here, we focused on SLC7A11 and GPX4 expressions in HSCs around fibrotic scars.…”

Section: Discussionmentioning

confidence: 99%

Sorafenib attenuates liver fibrosis by triggering hepatic stellate cell ferroptosis via HIF‐1α/SLC7A11 pathway

et al. 2021

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Objectives Evidences demonstrate that sorafenib alleviates liver fibrosis via inhibiting HSC activation and ECM accumulation. The underlying mechanism remains unclear. Ferroptosis, a novel programmed cell death, regulates diverse physiological/pathological processes. In this study, we aim to investigate the functional role of HSC ferroptosis in the anti‐fibrotic effect of sorafenib. Materials and Methods The effects of sorafenib on HSC ferroptosis and ECM expression were assessed in mouse model of liver fibrosis induced by CCl 4 . In vitro, Fer‐1 and DFO were used to block ferroptosis and then explored the anti‐fibrotic effect of sorafenib by detecting α‐SMA, COL1α1 and fibronectin proteins. Finally, HIF‐1α siRNA, plasmid and stabilizers were applied to assess related signalling pathway. Results Sorafenib attenuated liver injury and ECM accumulation in CCl 4 ‐induced fibrotic livers, accompanied by reduction of SLC7A11 and GPX4 proteins. In sorafenib‐treated HSC‐T6 cells, ferroptotic events (depletion of SLC7A11, GPX4 and GSH; accumulation iron, ROS and MDA) were discovered. Intriguingly, these ferroptotic events were not appeared in hepatocytes or macrophages. Sorafenib‐elicited HSC ferroptosis and ECM reduction were abrogated by Fer‐1 and DFO. Additionally, both HIF‐1α and SLC7A11 proteins were reduced in sorafenib‐treated HSC‐T6 cells. SLC7A11 was positively regulated by HIF‐1α, inactivation of HIF‐1α/SLC7A11 pathway was required for sorafenib‐induced HSC ferroptosis, and elevation of HIF‐1α could inhibit ferroptosis, ultimately limited the anti‐fibrotic effect. Conclusions Sorafenib triggers HSC ferroptosis via HIF‐1α/SLC7A11 signalling, which in turn attenuates liver injury and fibrosis.

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Section: Discussionmentioning

confidence: 99%

Sorafenib attenuates liver fibrosis by triggering hepatic stellate cell ferroptosis via HIF‐1α/SLC7A11 pathway

et al. 2021

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“…Recent research found that xCT mRNA levels were log-fold lower in primary mouse hepatocytes than in primary mouse HSCs. Inhibiting xCT in LX-2 cells by Erastin induced massive ferroptosis in HSCs did not affect hepatocytes [ 36 ]. Thus, we reasoned that MSC-ex-mediated xCT inhibition might preferentially promote LX-2 ferroptosis but not L-02 hepatocytes.…”

Section: Discussionmentioning

confidence: 99%

HucMSC-derived exosomes delivered BECN1 induces ferroptosis of hepatic stellate cells via regulating the xCT/GPX4 axis

et al. 2022

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Activated hepatic stellate cells (HSCs) are significant in liver fibrosis. Our past investigations have shown that human umbilical cord mesenchymal stem cells (hucMSCs) and their secreted exosomes (MSC-ex) could alleviate liver fibrosis via restraining HSCs activation. However, the mechanisms underlying the efficacy were not clear. Ferroptosis is a regulatory cell death caused by excessive lipid peroxidation, and it plays a vital role in the occurrence and development of liver fibrosis. In the present study, we aimed to study the proferroptosis effect and mechanism of MSC-ex in HSCs. MSC-ex were collected and purified from human umbilical cord MSCs. Proferroptosis effect of MSC-ex was examined in HSCs line LX-2 and CCl4 induced liver fibrosis in mice. Gene knockdown or overexpression approaches were used to investigate the biofactors in MSC-ex-mediated ferroptosis regulation. Results: MSC-ex could trigger HSCs ferroptosis by promoting ferroptosis-like cell death, ROS formation, mitochondrial dysfunction, Fe2+ release, and lipid peroxidation in human HSCs line LX-2. Glutathione peroxidase 4 (GPX4) is a crucial regulator of ferroptosis. We found that intravenous injection of MSC-ex significantly decreased glutathione peroxidase 4 (GPX4) expression in activated HSCs and collagen deposition in experimental mouse fibrotic livers. Mechanistically, MSC-ex derived BECN1 promoted HSCs ferroptosis by suppressing xCT-driven GPX4 expression. In addition, ferritinophagy and necroptosis might also play a role in MSC-ex-promoted LX-2 cell death. Knockdown of BECN1 in MSC diminished proferroptosis and anti-fibrosis effects of MSC-ex in LX-2 and fibrotic livers. MSC-ex may promote xCT/GPX4 mediated HSCs ferroptosis through the delivery of BECN1 and highlights BECN1 as a potential biofactor for alleviating liver fibrosis.

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“…Previous studies have shown that inhibition of system Xc- decreases cystine uptake and reduces its intracellular conversion to cysteine, impairing glutathione peroxidase 4 (GPX4) function. 39 Inhibition of system Xc- through salazosulfapyridine induces ferroptosis, whereas β-mercaptoethanol increases intracellular cystine uptake via HT1080, thereby inhibiting Erastin-induced ferroptosis. 40 SLC7A11 is the transport catalytic subunit in System Xc- and an important marker in ferroptosis.…”

Section: Discussionmentioning

confidence: 99%

Ferroptosis is Involved in Hyperoxic Lung Injury in Neonatal Rats

Jia¹,

Zheng²,

Zhou³

et al. 2021

JIR

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Purpose: To evaluate whether ferroptosis is involved in hyperoxic acute lung injury (HALI) and its mechanisms through the HALI model. Methods: HE staining was used to assess lung injury pathology after the establishment of neonatal rat HALI model. ELISA was used to detect ROS, GPX4, and GSH expression. Prussian blue staining and Western Blot were used to detect iron deposition and the expression of ferroptosis-related proteins, respectively. Results: The HALI group showed pathological changes with larger and fewer alveoli and thicker alveolar septa after HE staining. Prussian blue staining detected significant iron deposition in the lung tissue of the HALI group. GPX4, GSH, GSS, and SLC7A11 expressions were significantly decreased in the HALI group than in the normal control group. In contrast, ROS, TFRC, FHC, and FLC expressions showed opposite results (p<0.05). Conclusion:Ferroptosis may be involved in the pathological process of hyperoxic lung injury in neonatal rats.

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Inhibiting xCT/SLC7A11 induces ferroptosis of myofibroblastic hepatic stellate cells but exacerbates chronic liver injury

Cited by 34 publications

References 45 publications

Sorafenib attenuates liver fibrosis by triggering hepatic stellate cell ferroptosis via HIF‐1α/SLC7A11 pathway

Sorafenib attenuates liver fibrosis by triggering hepatic stellate cell ferroptosis via HIF‐1α/SLC7A11 pathway

HucMSC-derived exosomes delivered BECN1 induces ferroptosis of hepatic stellate cells via regulating the xCT/GPX4 axis

Ferroptosis is Involved in Hyperoxic Lung Injury in Neonatal Rats

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