SIRT1-FOXO3 Pathway reprograms fatty acid metabolism to Mitigate Ferroptosis and Fibrosis

Targeting ferroptosis with reductive agents has emerged as a promising strategy to mitigate fibrotic diseases in various pathological conditions. However, while the NAD+/NADH redox pair plays a crucial role in biological processes, its connection to ferroptosis beyond FSP1 remains poorly understood. To explore underappreciated NAD+/NADH-dependent factors in the ferroptosis cascade, we conducted a compound screening of 138 NAD+ enzyme modulatory molecules and identified Sirtuin-1 (SIRT1) activators as critical regulators of ferroptosis. SIRT1 activators, such as SRT1720, broadly inhibit ferroptosis by reducing lipid peroxidation without affecting labile iron levels. Moreover, SRT1720 effectively alleviates pulmonary and liver fibrosis in mouse models. Using ChIP-seq and validation assays, we demonstrated that FOXO3 binds to gene loci involved in fatty acid elongation and arachidonic acid metabolism in ferroptosis. SRT1720 disrupts this binding, thereby restraining fatty acid metabolism and limiting lipid peroxides production. Our findings establish the SIRT1-FOXO3 axis as a key inhibitory pathway against ferroptosis and highlight its therapeutic potential for ferroptosis-associated diseases, including fibrosis.

采用还原剂靶向铁死亡（ferroptosis）已成为缓解多种病理状态下纤维化疾病的颇具前景的策略。然而，尽管NAD+/NADH氧化还原对在生物学过程中发挥关键作用，但其与铁死亡的关联除FSP1外仍不甚明晰。为探索铁死亡级联反应中未被充分认知的NAD+/NADH依赖型调控因子，我们对138种NAD+酶调节分子开展了化合物筛选，并鉴定出Sirtuin-1（SIRT1）激活剂作为铁死亡的关键调控因子。以SRT1720为代表的SIRT1激活剂可通过抑制脂质过氧化广泛阻断铁死亡，且不会影响不稳定铁水平。此外，SRT1720可有效缓解小鼠模型中的肺纤维化与肝纤维化。借助染色质免疫共沉淀测序（ChIP-seq）与验证实验，我们证实叉头框转录因子O3（FOXO3）可结合铁死亡过程中参与脂肪酸延伸与花生四烯酸代谢的基因位点。SRT1720可破坏该结合过程，进而抑制脂肪酸代谢并减少脂质过氧化物的生成。本研究确立了SIRT1-FOXO3轴作为抗铁死亡的关键抑制通路，并凸显了其在包括纤维化在内的铁死亡相关疾病中的治疗潜力。