Angiotensin-(1–7) attenuates collagen-induced arthritis and suppresses ferroptosis in THP-1-derived macrophages: involvement of p53/SLC7A11 signaling

Abstract

Rheumatoid arthritis (RA) is characterized by persistent synovial inflammation and progressive joint destruction, while ferroptosis has emerged as a potential contributor to inflammatory tissue injury. This study investigated whether angiotensin-(1–7) [Ang-(1–7)] attenuates arthritis by regulating ferroptosis and explored the involvement of p53/solute carrier family 7 member 11 (SLC7A11) signaling. Bioinformatic analysis of the GSE55235 dataset was performed to identify ferroptosis-related differentially expressed genes in RA. A collagen-induced arthritis (CIA) mouse model and erastin-treated THP-1-derived macrophages were used to evaluate the effects of Ang-(1–7) in vivo and in vitro. Ferroptosis-related genes in RA were enriched in inflammatory responses, oxidative stress, ferroptosis, and p53 signaling. In CIA mice, Ang-(1–7) reduced paw swelling and arthritis scores, ameliorated synovial inflammation and joint damage, and attenuated iron deposition, lipid peroxidation, and ferroptosis-related molecular alterations. Double-immunofluorescence staining further demonstrated decreased glutathione peroxidase 4 (GPX4) and increased acyl-CoA synthetase long-chain family member 4 (ACSL4) expression in F4/80-positive macrophage areas in CIA joints, both of which were reversed by Ang-(1–7). In erastin-treated THP-1-derived macrophages, Ang-(1–7) improved cell viability, restored glutathione levels, reduced malondialdehyde, reactive oxygen species, lipid reactive oxygen species, and Fe²⁺ accumulation, alleviated mitochondrial injury, and reversed ferroptosis-related molecular abnormalities. Nutlin-3 A-mediated p53 stabilization partially weakened these protective effects, whereas TP53 knockdown diminished the additional protective response to Ang-(1–7). These findings suggest that Ang-(1–7) attenuates ferroptosis-related joint injury in CIA mice and suppresses erastin-induced ferroptosis in THP-1-derived macrophages, with these effects being partially associated with modulation of p53/SLC7A11 signaling.