ArticleLiver international : official journal of the International Association for the Study of the Liver2021
Inhibiting xCT/SLC7A11 induces ferroptosis of myofibroblastic hepatic stellate cells but exacerbates chronic liver injury.
Article in Liver international : official journal of the International Association for the Study of the Liver, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 42 papers.
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Who cites it
42 citing papers in PubMed, 54 citations in OpenAlex.
- Ferroptosis in liver biology and diseases.Hepatology communications · 2026Review
- Pirfenidone Sensitizes Hepatic Stellate Cells to Ferroptosis by Reprogramming Glutamine and Serine Metabolism for GSH Depletion.Antioxidants (Basel, Switzerland) · 2026Article
- HMGB1-mediated enhancement of glycolysis activates hepatic stellate cells by inhibiting ferroptosis in alcoholic hepatic fibrosis.Stem cell research & therapy · 2026Article
- Ferroptosis in liver diseases: molecular mechanisms, biomarker potential, and clinical translation.Frontiers in cell and developmental biology · 2026Review
- Ferroptosis-The "Double-Edged Sword" in Cancer: Mechanisms of Tumor Suppression/Resistance and Therapeutic Manipulation.Biology · 2025Review
- Mitochondrial HSP90 Paralog TRAP1 Deletion Drives Glutamine Addiction in Tumor Cells via Destablization of the Cys/Glu Antiporter SLC7A11/xCT.Molecular cancer research : MCR · 2025Article
- Astragalin promotes HSCs ferroptosis through NCOA4 mediated ferritinophagy to alleviate liver fibrosis in zebrafish and mice.Communications biology · 2025Article
- Erk1/2 Orchestrates SSPH I-Induced Oxidative Stress, Mitochondrial Dysfunction and Ferroptosis in Hepatocellular Carcinoma.Journal of cellular and molecular medicine · 2025Article
- Ferroptosis in immune chaos: Unraveling its impact on disease and therapeutic potential.Journal of physiology and biochemistry · 2025Review
- Inhibition of mitochondrial complex I induces mitochondrial ferroptosis by regulating CoQH2 levels in cancer.Cell death & disease · 2025Article
- SLC7A11 in Fibrosis: Molecular Mechanisms and Future Prospects.Aging and disease · 2025Review
- The Role of Solute Carrier Family Transporters in Hepatic Steatosis and Hepatic Fibrosis.Journal of clinical and translational hepatology · 2025Review
- Review
- Regulation of SLC7A11 by LncRNA GPRC5D-AS1 mediates ferroptosis in skeletal muscle: Mechanistic exploration of sarcopenia.Frontiers in molecular biosciences · 2025Article
- Prognostic Values of Ferroptosis-Related Proteins ACSL4, SLC7A11, and CHAC1 in Cholangiocarcinoma.Biomedicines · 2024Article
- Canagliflozin Inhibits Palmitic Acid-Induced Vascular Cell Aging In Vitro through ROS/ERK and Ferroptosis Pathways.Antioxidants (Basel, Switzerland) · 2024Article
- Plasticity, heterogeneity, and multifunctionality of hepatic stellate cells in liver pathophysiology.Hepatology communications · 2024Review
- Naringenin alleviates liver fibrosis by triggering autophagy-dependent ferroptosis in hepatic stellate cells.Heliyon · 2024Article
- Emerging role of ferroptosis in metabolic dysfunction-associated steatotic liver disease: revisiting hepatic lipid peroxidation.EBioMedicine · 2024Review
- Ferroptosis: a potential target for the treatment of atherosclerosis.Acta biochimica et biophysica Sinica · 2024Review
Corrections and comments
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
Abstract
BACKGROUND &
aimsThe outcome of liver injury is dictated by factors that control the accumulation of myofibroblastic (activated) hepatic stellate cells (MF-HSCs) but therapies that specifically block this process have not been discovered. We evaluated the hypothesis that MF-HSCs and liver fibrosis could be safely reduced by inhibiting the cysteine/glutamate antiporter xCT.
methodsxCT activity was disrupted in both HSC lines and primary mouse HSCs to determine its effect on HSC biology. For comparison, xCT expression and function were also determined in primary mouse hepatocytes. Finally, the roles of xCT were assessed in mouse models of liver fibrosis.
resultsWe found that xCT mRNA levels were almost a log-fold higher in primary mouse HSCs than in primary mouse hepatocytes. Further, primary mouse HSCs dramatically induced xCT as they became MF, and inhibiting xCT blocked GSH synthesis, reduced growth and fibrogenic gene expression and triggered HSC ferroptosis. Doses of xCT inhibitors that induced massive ferroptosis in HSCs had no effect on hepatocyte viability in vitro, and xCT inhibitors reduced liver fibrosis without worsening liver injury in mice with acute liver injury. However, TGFβ treatment up-regulated xCT and triggered ferroptosis in cultured primary mouse hepatocytes. During chronic liver injury, xCT inhibitors exacerbated injury, impaired regeneration and failed to improve fibrosis, confirming that HSCs and hepatocytes deploy similar mechanisms to survive chronic oxidative stress.
conclusionsInhibiting xCT can suppress myofibroblastic activity and induce ferroptosis of MF-HSCs. However, targeting xCT inhibition to MF-HSCs will be necessary to exploit ferroptosis as an anti-fibrotic strategy.
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