Liang_2025_Funct.Integr.Genomics_25_156

Peroxiredoxin 6 (PRDX6) is widely acknowledged as a suppressor of ferroptosis, and recent studies have demonstrated that inhibition of macrophage ferroptosis can alleviate sepsis-associated acute lung injury (SA-ALI). Nonetheless, the specific involvement of PRDX6 in regulating macrophage ferroptosis during SA-ALI remains unexplored. This study aims to elucidate the mechanistic role of PRDX6 in modulating macrophage ferroptosis within the context of SA-ALI. Mouse alveolar macrophages (MH-S cells) were infected with either a PRDX6 overexpression lentivirus or a ZC3H13 knockdown lentivirus prior to lipopolysaccharide (LPS) treatment. In vivo, mice were treated with the same lentiviral constructs and subjected to a SA-ALI model via cecal ligation and puncture (CLP). This study demonstrates that PRDX6 overexpression or ZC3H13 knockdown significantly attenuated LPS-induced ferroptosis in alveolar macrophages and alleviated lung injury in CLP-induced SA-ALI mouse models. However, simultaneous knockdown of both ZC3H13 and PRDX6 abolished the protective effect conferred by ZC3H13 silencing, indicating that PRDX6 mediates the anti-ferroptotic role of ZC3H13 inhibition. Mechanistically, PRDX6 suppresses p53 expression, thereby upregulating SLC7A11 and inhibiting ferroptosis. Additionally, ZC3H13 promotes the m6A modification of PRDX6 mRNA, which facilitates its degradation in a YTHDF2-dependent manner, ultimately leading to reduced PRDX6 expression. Overall, these findings demonstrate that the methyltransferase ZC3H13 modulates PRDX6 expression by elevating the m6A methylation level of PRDX6 mRNA in a YTHDF2-dependent manner, thereby influencing the p53/SLC7A11 axis and promoting ferroptosis in alveolar macrophages, ultimately contributing to the progression of SA-ALI.