Abstract

Objective Diabetic cardiomyopathy (DCM) is characterized by metabolic dysfunction and lipotoxicity. The roles of acyl-CoA thioesterase 1 (ACOT1) and the novel post-translational modification lactylation in its pathogenesis remain unclear. This study aimed to investigate the stage-specific function of ACOT1 and the mechanism by which lactylation of SREBP1c regulates lipid metabolism in DCM. Methods Key genes were screened via bioinformatic analysis. ACOT1 was functionally assessed in early and decompensated DCM mouse models using gain- and loss-of-function strategies, evaluated by echocardiography and hemodynamics. SREBP1c lactylation was identified by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and validated via site-directed mutagenesis. Results ACOT1 exhibited a biphasic expression pattern: protective upregulation in early DCM improved cardiac function and attenuated oxidative stress, whereas its downregulation in decompensated DCM exacerbated remodeling and dysfunction. Mechanistically, ACOT1 physically interacted with SREBP1c and facilitated its lactylation under high-lactate conditions. This modification was essential for SREBP1c transcriptional activity, driving its nuclear translocation and subsequent upregulation of the fatty acid transporter CD36. The enhanced CD36-mediated uptake led to free fatty acid accumulation, aggravating myocardial lipotoxicity and DCM progression. Conclusion This study reveals a dual-stage regulatory role of ACOT1 in DCM and identifies a novel ACOT1-SREBP1c(lactylation)-CD36 axis linking metabolic reprogramming to lipotoxic injury. These findings establish lactylation as a key regulatory mechanism in diabetic heart metabolism and propose ACOT1 and SREBP1c lactylation as potential therapeutic targets for mitigating myocardial lipotoxicity in DCM.