Abstract：
Acute lung injury (ALI) is a serious disorder characterized by the release of pro-inflammatory cytokines and cascade activation of macrophages. Ferroptosis, a form of iron-dependent cell death triggered by intracellular phospholipid peroxidation, has been implicated as an internal mechanism underlying ALI. In this study, we investigated the effects of m6A demethylase fat mass and obesity-associated protein (FTO) on the inhibition of macrophage ferroptosis in ALI. Using a mouse model of lipopolysaccharide (LPS)-induced ALI, we observed the induction of ferroptosis and its co-localization with the macrophage marker F4/80, suggesting that ferroptosis might be induced in macrophages. Ferroptosis was promoted during LPS-induced inflammation in macrophages in vitro, and the inflammation was counteracted by the ferroptosis inhibitor ferrostatin-1 (fer-1). Given that FTO showed lower expression levels in the lung tissue of mice with ALI and inflammatory macrophages, we further dissected the regulatory capacity of FTO in ferroptosis. The results demonstrated that FTO alleviated macrophage inflammation by inhibiting ferroptosis. Mechanistically, FTO decreased the stability of ACSL4 mRNA via YTHDF1, subsequently inhibiting ferroptosis and inflammation by interrupting polyunsaturated fatty acid consumption. Moreover, FTO downregulated the synthesis and secretion of prostaglandin E2, thereby reducing ferroptosis and inflammation. In vivo, the FTO inhibitor FB23-2 aggravated lung injury, the inflammatory response, and ferroptosis in mice with ALI; however, fer-1 therapy mitigated these effects. Overall, our findings revealed that FTO may function as an inhibitor of the inflammatory response driven by ferroptosis, emphasizing its potential as a target for ALI treatment.
摘要：
急性肺损伤（ALI）是一种严重的疾病，其特征是促炎细胞因子的释放和巨噬细胞的级联激活。Ferroptosis,一种由细胞内磷脂过氧化引发的铁依赖性细胞死亡，被认为是ALI的内在机制。在这项研究中,我们研究了m6A脱甲基酶脂肪量和肥胖相关蛋白（FTO）对ALI中巨噬细胞铁凋亡的抑制作用。使用脂多糖（LPS）诱导的ALI的小鼠模型，我们观察到铁凋亡的诱导及其与巨噬细胞标记F4/80的共定位，表明在巨噬细胞中可能诱导铁凋亡。在体外LPS诱导的巨噬细胞炎症过程中促进Ferroptosis,并且炎症被铁凋亡抑制剂Feratin-1（Fer-1）抵消。鉴于FTO在ALI和炎性巨噬细胞小鼠的肺组织中显示较低的表达水平,我们进一步剖析了FTO在铁凋亡中的调节能力。结果表明，FTO通过抑制铁凋亡减轻巨噬细胞炎症。机械上,FTO通过YTHDF1降低ACSL4mRNA的稳定性，随后通过中断多不饱和脂肪酸的消耗来抑制铁凋亡和炎症。此外，FTO下调前列腺素E2的合成和分泌,从而减少铁凋亡和炎症。在体内,FTO抑制剂FB23-2加重肺损伤，炎症反应，ALI小鼠的铁死亡；然而，FER-1疗法减轻了这些影响。总的来说,我们的发现表明，FTO可能是铁凋亡引起的炎症反应的抑制剂，强调其作为ALI治疗靶点的潜力。
