Liang Jifang, Liu Zemin, He Yajun, Li Heihei, Wu Weidong
Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, No. 99, Longcheng Street, Xuaodian District, Taiyuan, 030032, Shanxi, China.
Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Third Hospital of Shanxi Medical University, Tongji Shanxi Hospital, Taiyuan, 030032, China.
Funct Integr Genomics. 2025 Jul 12;25(1):156. doi: 10.1007/s10142-025-01659-1.
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.
过氧化物酶体增殖物激活受体6（PRDX6）被广泛认为是铁死亡的抑制因子，最近的研究表明，抑制巨噬细胞铁死亡可以减轻脓毒症相关急性肺损伤（SA-ALI）。然而，PRDX6在SA-ALI期间调节巨噬细胞铁死亡中的具体作用仍未得到探索。本研究旨在阐明PRDX6在SA-ALI背景下调节巨噬细胞铁死亡的机制作用。在脂多糖（LPS）处理之前，用PRDX6过表达慢病毒或ZC3H13敲低慢病毒感染小鼠肺泡巨噬细胞（MH-S细胞）。在体内，用相同的慢病毒构建体处理小鼠，并通过盲肠结扎和穿刺（CLP）建立SA-ALI模型。本研究表明，PRDX6过表达或ZC3H13敲低显著减轻了LPS诱导的肺泡巨噬细胞铁死亡，并减轻了CLP诱导的SA-ALI小鼠模型中的肺损伤。然而，同时敲低ZC3H13和PRDX6消除了ZC3H13沉默所赋予的保护作用，表明PRDX6介导了ZC3H13抑制的抗铁死亡作用。机制上，PRDX6抑制p53表达，从而上调SLC7A11并抑制铁死亡。此外，ZC3H13促进PRDX6 mRNA的m6A修饰，以YTHDF2依赖的方式促进其降解，最终导致PRDX6表达降低。总体而言，这些发现表明，甲基转移酶ZC3H13通过以YTHDF2依赖的方式提高PRDX6 mRNA的m6A甲基化水平来调节PRDX6表达，从而影响p53/SLC7A11轴并促进肺泡巨噬细胞铁死亡，最终导致SA-ALI的进展。
