METTL14 alleviates sepsis-induced acute kidney injury by targeting Hmox1-mediated ferroptosis through m6A modification.

The m6A methyltransferase METTL14 plays a role in cellular stress responses, but its function in sepsis-associated acute kidney injury (S-AKI) remains unclear. This study investigates METTL14’s involvement in regulating ferroptosis and inflammation through HMOX1 in S-AKI. We analyzed renal tissues from S-AKI patients and a CLP-induced murine model for histological and molecular changes. In vitro, LPS-treated HK-2 cells were used to mimic S-AKI, with METTL14 expression manipulated via lentiviral transfection. Ferroptosis and inflammatory responses were evaluated using ELISA, qPCR, immunohistochemistry, and western blotting. ROS and lipid peroxidation were assessed with C11-BODIPY, while MeRIP and actinomycin D assays explored m6A modification and mRNA stability of HMOX1. Survival outcomes were assessed over 7 days post-CLP surgery. HMOX1 modulation was further examined using Hemin (inducer) and ZnPP (inhibitor) in vivo. METTL14 was significantly downregulated in both human S-AKI patient tissues and murine CLP models. Its overexpression improved renal function, reduced histological injury and mortality, and suppressed pro-inflammatory cytokines (IL-6, IL-1β, TNF-α). Mechanistically, we identified METTL14 as a novel regulator of HMOX1, promoting its m6A-dependent degradation and thereby limiting iron accumulation and lipid peroxidation associated with ferroptosis. This regulatory axis was confirmed by pharmacological modulation, where Hemin reversed METTL14’s protective effects, while ZnPP rescued METTL14-deficient mice. Additionally, METTL14 reduced ROS generation and stabilized redox homeostasis. METTL14 protects against S-AKI by suppressing ferroptosis via m6A-dependent regulation of HMOX1. These findings reveal a novel epitranscriptomic pathway and suggest METTL14 as a promising therapeutic target for S-AKI.