Abstract / Summary
The epigenetic mechanisms driving the transition to ferroptosis in acute kidney injury (AKI) remain unclear. In this study, protein methyltransferase 5 (PRMT5) and its partner MEP50 were significantly upregulated in the renal tubules of AKI patients and murine models. Genetic silencing of PRMT5 via AAV-shRNA in vivo and siRNA in vitro improved renal function, attenuated mitochondrial damage, and suppressed ferroptotic tubular cell death. Mechanistically, PRMT5 promotes ACSL4 expression in a WDR5-dependent manner, facilitating tubular ferroptosis. Pharmacological inhibition of PRMT5 (GSK591) post-treatment or cloperastine hydrochloride prophylactic administration similarly improved renal function and limited ferroptotic cell death. These findings offer novel insights into the upstream epigenetic regulation of ACSL4-driven ferroptosis and suggest that PRMT5-ACSL4 axis might be a potential therapeutic target for AKI intervention.