Sirt1 deficiency promotes age-related heart failure through enhancing ferroptosis via GATA4-HADHA-GPX4 axis

Abstract Aging is a major contributor to the escalating prevalence of heart failure (HF). Ferroptosis has been implicated in age-related disorders and cardiovascular diseases.The role of ferroptosis in age-related HF and the underlying mechanisms remain ambiguous. Herein, we found that aging rats displayed compromised cardiac function, with molecular characteristics indicative of ferroptosis, including diminished glutathione peroxidase 4 (GPX4) levels and heightened lipid peroxidation. Notably, a high-iron diet exacerbated ferroptosis and promoted cardiac dysfunction, while ferrostatin-1, a specific ferroptosis inhibitor, rescued this phenotype. Proteomic data analysis uncovered that the expression of hydroxyacyl-CoA dehydrogenase subunit A (HADHA) was significantly reduced in aging rats fed a high-iron diet. HADHA deficiency resulted in mitochondrial dysfunction and an accumulation of reactive oxygen species, leading to glutathione (GSH) exhaustion, causing the downregulation of GPX4 and subsequent ferroptosis. Furthermore, it was confirmed that the reduction of Sirt1 in the hearts of aging rats caused the downregulation of HADHA by binding and inhibited the expression of GATA4, a transcription factor of HADHA, as evidenced by co-immunoprecipitation experiments. Furthermore, resveratrol, a Sirt1 agonist, effectively shielded aging rats from HF by upregulating HADHA and mitigating ferroptosis. In conclusion, this study underscores the significance of ferroptosis in age-related HF, and suggests that targeting HADHA or Sirt1 may present potential strategies for the prevention and treatment of age-related HF.