Supplementary file 1_4-Methylcatechol attenuates diabetic myocardial disorder via the ESR1–PI3K–AKT pathway.docx

ContextDiabetic myocardial disorder is a severe complication of diabetes mellitus, in which hyperglycemia and hyperlipidemia play pivotal roles in its pathogenesis.
ObjectiveThis study aimed to investigate the protective effects of 4-methylcatechol (4-MC) against diabetic myocardial injury and to elucidate its underlying mechanisms, using a high glucose and palmitic acid (HG/PA)-induced AC16 cardiomyocyte injury model. Materials and methods: To investigate 4-Methylcatechol (4-MC), potential therapeutic targets were first identified via bioinformatics, followed by molecular docking to analyze binding to the core target and KEGG/GO enrichment analyses to identify critical pathways, with final in vitro validation in AC16 cells assessing effects on HG/PA-induced oxidative stress and apoptosis, using pharmacological inhibitors to confirm the specific signaling axis.
ResultsBioinformatics analysis identified ESR1 as a potential core therapeutic target of 4-MC. Molecular docking revealed that 4-MC forms stable hydrogen bonds with Arg394 and Lys449 residues within the ESR1 binding pocket. KEGG/GO enrichment analyses further indicated that the modulation of oxidative stress, apoptosis, and energy metabolism constitutes the critical pathways mediating 4-MC’s therapeutic effects. In vitro experiments demonstrated that 4-MC significantly mitigates HG/PA-induced oxidative stress and intrinsic apoptosis in cardiomyocytes. Notably, this cardioprotection was abolished upon treatment with the ESR1 antagonist Fulvestrant or the PI3K inhibitor LY294002, validating that 4-MC exerts its protective effect specifically through the ESR1-PI3K-AKT signaling axis.
Conclusion4-Methylcatechol alleviates diabetic myocardial disorder by activating the ESR1-PI3K-AKT pathway, offering novel therapeutic targets and a candidate compound for intervention.