The STAT1–IRF1–ACSL4 axis drives peritoneal fibrosis and ferroptosis via lipid peroxidation-dependent mechanisms

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.