The STAT1–IRF1–ACSL4 axis drives peritoneal fibrosis and ferroptosis via lipid peroxidation-dependent mechanisms
- 1Department of Nephrology, Taihe Hospital, Affiliated Hospital of Hubei University of Medicine, Shiyan, China
Abstract
Peritoneal fibrosis, a major complication of long-term peritoneal dialysis, is driven by transforming growth factor-β1 (TGF-β1)-mediated mesothelial cell dysfunction. Emerging evidence links ferroptosis—a lipid peroxidation-dependent cell death—to fibrotic diseases, but the molecular mechanisms in peritoneal pathology remain unclear. Here, we investigate the role of the STAT1–IRF1–ACSL4 axis in TGF-β1-induced fibrosis and ferroptosis in human peritoneal mesothelial cells (HPMCs). HPMCs were stimulated with TGF-β1 to establish an in vitro fibrosis model and subjected to ACSL4 knockdown, ACSL4 overexpression, or ferroptosis inhibition with Ferrostatin-1. TGF-β1 significantly upregulated fibrosis markers (α-SMA, Collagen I), ferroptosis-related proteins (MDA, 4-HNE, PTGS2), and the STAT1–IRF1 signaling pathway, while suppressing the antioxidant system (GPX4, SLC7A11) (P < 0.001). ACSL4 knockdown markedly restored cell viability, reduced lipid peroxidation, Fe2+ accumulation, ferroptosis activation, and inflammatory cytokine secretion (IL-1β, IL-18) (P < 0.001). In contrast, ACSL4 overexpression exacerbated TGF-β1-induced ferroptosis, fibrosis, and inflammation. Mechanistically, ACSL4 regulated activation of the STAT1–IRF1 axis, as evidenced by changes in STAT1 phosphorylation and IRF1 nuclear translocation. Notably, Ferrostatin-1 reversed ACSL4-induced lipid peroxidation, inhibited STAT1–IRF1 activation, restored GPX4 expression, and attenuated fibrotic and inflammatory responses (P < 0.01). Collectively, these findings demonstrate that the STAT1–IRF1–ACSL4 axis integrates lipid peroxidation-dependent ferroptosis with pro-fibrotic and pro-inflammatory signaling in peritoneal mesothelial cells, identifying ACSL4-centered ferroptotic signaling as a potential therapeutic target for peritoneal fibrosis.
Clinical trial number: Not applicable.
Related
- Beyond Weight Loss and Glycemic Control: Molecular Mechanisms and Hypothesis-Generating Therapeutic Potential of Incretin-Based Therapies Against Peritoneal Fibrosis in Peritoneal Dialysis.
- Relationship between transforming growth factor-β1， microRNA-29c in peritoneal dialysate and peritoneal fibrosis in patients with glomerular diseases receiving peritoneal dialysis
- The clinical value of 68Ga-FAPI to evaluate the peritoneal fibrosis and its inherent molecule relationship with POSTN and DPP7
- SGLT-2 expression increases with glucose concentration and duration of high-glucose peritoneal dialysis solution, exacerbating peritoneal fibrosis, inflammation, and vascular lesions
- Discovering ferroptosis in biliary epithelium during liver fibrosis
BibTeX
@article{cheng2026stat1irf1acsl4,
title = {{The STAT1–IRF1–ACSL4 axis drives peritoneal fibrosis and ferroptosis via lipid peroxidation-dependent mechanisms}},
author = {Peng Cheng and Qinghong Zhang},
journal = {Renal Failure},
year = {2026},
month = oct,
doi = {10.1080/0886022x.2026.2748098},
url = {https://doi.org/10.1080/0886022x.2026.2748098},
note = {CC BY-NC 4.0},
}
RIS
TY - JOUR
TI - The STAT1–IRF1–ACSL4 axis drives peritoneal fibrosis and ferroptosis via lipid peroxidation-dependent mechanisms
AU - Peng Cheng
AU - Qinghong Zhang
PY - 2026
DA - 2026/10/30
JO - Renal Failure
DO - 10.1080/0886022x.2026.2748098
UR - https://doi.org/10.1080/0886022x.2026.2748098
AB - Peritoneal fibrosis, a major complication of long-term peritoneal dialysis, is driven by transforming growth factor-β1 (TGF-β1)-mediated mesothelial cell dysfunction. Emerging evidence links ferroptosis—a lipid peroxidation-dependent cell death—to fibrotic diseases, but the molecular mechanisms in peritoneal pathology remain unclear. Here, we investigate the role of the STAT1–IRF1–ACSL4 axis in TGF-β1-induced fibrosis and ferroptosis in human peritoneal mesothelial cells (HPMCs). HPMCs were stimulated with TGF-β1 to establish an in vitro fibrosis model and subjected to ACSL4 knockdown, ACSL4 overexpression, or ferroptosis inhibition with Ferrostatin-1. TGF-β1 significantly upregulated fibrosis markers (α-SMA, Collagen I), ferroptosis-related proteins (MDA, 4-HNE, PTGS2), and the STAT1–IRF1 signaling pathway, while suppressing the antioxidant system (GPX4, SLC7A11) (P < 0.001). ACSL4 knockdown markedly restored cell viability, reduced lipid peroxidation, Fe2+ accumulation, ferroptosis activation, and inflammatory cytokine secretion (IL-1β, IL-18) (P < 0.001). In contrast, ACSL4 overexpression exacerbated TGF-β1-induced ferroptosis, fibrosis, and inflammation. Mechanistically, ACSL4 regulated activation of the STAT1–IRF1 axis, as evidenced by changes in STAT1 phosphorylation and IRF1 nuclear translocation. Notably, Ferrostatin-1 reversed ACSL4-induced lipid peroxidation, inhibited STAT1–IRF1 activation, restored GPX4 expression, and attenuated fibrotic and inflammatory responses (P < 0.01). Collectively, these findings demonstrate that the STAT1–IRF1–ACSL4 axis integrates lipid peroxidation-dependent ferroptosis with pro-fibrotic and pro-inflammatory signaling in peritoneal mesothelial cells, identifying ACSL4-centered ferroptotic signaling as a potential therapeutic target for peritoneal fibrosis. Clinical trial number: Not applicable.
SN - 0886-022X
SN - 1525-6049
ER -