Hongqi Shenmai Decoction ameliorates post-myocardial infarction heart failure by preserving mitochondrial cardiolipin homeostasis via attenuation of EGFR/JAK2-STAT3 signaling.

BACKGROUND: Post-myocardial infarction heart failure (post-MI HF) is driven by adverse ventricular remodeling and mitochondrial dysfunction. Cardiolipin is essential for mitochondrial integrity, but its upstream regulation in failing myocardium remains unclear. Whether Hongqi Shenmai Decoction (HQSMD) preserves cardiolipin homeostasis through epidermal growth factor receptor (EGFR)/Janus kinase 2 (JAK2)-signal transducer and activator of transcription 3 (STAT3) signaling has not been defined. PURPOSE: To determine whether HQSMD alleviates post-MI HF by preserving cardiolipin-related metabolic homeostasis through modulation of the EGFR/JAK2-STAT3 pathway. STUDY DESIGN: An in vivo post-MI HF mouse model and an in vitro oxygen-glucose deprivation/reoxygenation (OGD/R)-injured AC16 cardiomyocyte model were integrated with chemical profiling, multi-omics analysis, target validation, and epidermal growth factor (EGF)-mediated rescue experiments. METHODS: Cardiac function, infarct injury, fibrosis, oxidative stress, mitochondrial ultrastructure, and mitochondrial function were assessed. Ultra-performance liquid chromatography-mass spectrometry, transcriptomics, untargeted metabolomics, molecular docking, surface plasmon resonance, western blotting, immunofluorescence, and cardiolipin-related functional assays were performed. RESULTS: HQSMD improved cardiac function and attenuated infarction, remodeling, oxidative stress, and mitochondrial injury in post-MI HF mice. Multi-omics analyses implicated EGFR/JAK-STAT signaling and cardiolipin-related glycerophospholipid disturbances. HQSMD suppressed MI- or OGD/R-induced phosphorylation of EGFR, JAK2, and STAT3 Tyr705 while preserving mitochondrial STAT3/Ser727 signaling. In cardiomyocytes, HQSMD reduced apoptosis and restored mitochondrial dynamics, biogenesis, redox balance, membrane potential, mPTP function, cardiolipin-associated fluorescence, and cardiolipin-related enzyme expression. EGF partially reversed these effects. CONCLUSION: HQSMD protects against post-MI HF mainly by attenuating pathological EGFR/JAK2-dependent STAT3 Tyr705 activation, thereby preserving cardiolipin-related metabolic homeostasis and mitochondrial integrity.