Abstract Fibrosis contributes to approximately 16-20% of global mortality, largely due to its pivotal role in organ failure and cancer progression. Pulmonary fibrosis—a devastating condition marked by extracellular matrix accumulation, tissue destruction, and chronic lung inflammation—exemplifies the severe clinical burden of fibrotic diseases, characterized by high healthcare costs and dismal survival rates. Consequently, targeting fibrotic pathways has emerged as a promising therapeutic avenue for diverse pathologies.Among proposed mechanisms driving fibrosis, Ferroptosis, defined as iron-dependent lipid peroxidation leading to membrane rupture and cell death, has garnered particular attention for its role in fibrosis. Although current ferroptosis inhibitors show efficacy in preclinical models, a deeper mechanistic understanding is essential to develop targeted therapies for ferroptosis-driven pathologies. 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. This abstract is funded by: no
Chen et al. (Fri,) studied this question.