Functional and mechanistic study on toddalolactone in diabetic cardiomyopathy based on multi-omics approaches

Background Diabetic cardiomyopathy (DCM) remains a major clinical challenge due to the absence of metabolism-targeted therapeutics. This study investigates the therapeutic potential of toddalolactone in DCM and elucidates its underlying molecular mechanism. Methods A network pharmacology approach was employed to identify candidate targets of toddalolactone. An in vitro sodium palmitate-induced injury model in HL-1 cardiomyocytes was established to assess cellular functional responses. Integrated transcriptomic and metabolomic profiling was performed to characterize metabolic dysregulation and recovery. Target engagement was validated through molecular docking, cellular thermal shift assay, and Western blotting. In vivo efficacy was evaluated in a high-fat diet/streptozotocin-induced murine DCM model, with outcomes assessed via serum biochemical assays, echocardiography, and histopathological analysis. Results PKCα was identified as a candidate therapeutic target. In vitro , toddalolactone significantly improved cardiomyocyte viability, restored ATP production, and attenuated lipid accumulation and oxidative stress. Multi-omics integration revealed that toddalolactone ameliorated glycerophospholipid metabolism disorder and mitochondrial energy deficits, an effect associated with the modulation of the PKCα signaling pathway. Biochemical and biophysical assays supported the interaction of toddalolactone with PKCα and the subsequent regulation of its downstream effectors. In vivo , toddalolactone treatment corrected dyslipidemia, improved left ventricular systolic function, and mitigated cardiac hypertrophy and interstitial fibrosis. Conclusion Toddalolactone may be associated with mitigation of DCM phenotypes, potentially through interaction with modulation of the PKCα signaling pathway, which correlates with improved cardiac metabolic status and attenuated remodeling, suggesting its potential as a candidate therapeutic lead for DCM.