Glabridin attenuates diabetic cardiomyopathy by activating AMPK to suppress ferroptosis and TGF-β-mediated myocardial fibrosis.

While glabridin (GLA), a bioactive component from Glycyrrhiza glabra, is known to ameliorate diabetes-associated diseases, its specific role in diabetic cardiomyopathy (DbCM) remains largely unexplored. Accordingly, this work aimed to determine whether GLA exerts therapeutic effects against DbCM and to elucidate the underlying mechanism. H9c2 cardiomyocytes were exposed to a hyperglycemic and hyperlipidemic (HGHP) environment to establish an in vitro DbCM cell model, using high glucose and palmitic acid stimulation. Cell viability, apoptosis, lactate dehydrogenase release, microscale malondialdehyde and iron content, as well as ferroptosis-related biomarkers, were evaluated. A target interaction network for GLA against DbCM was constructed using a network pharmacology approach. Streptozotocin-induced diabetic mouse models were employed to assess the protective effect of GLA on the heart. GLA protected H9c2 cardiomyocytes against HGHP-induced morphological alterations, cytotoxicity, apoptosis, ferroptosis, and fibrosis. A total of seventy-three overlapping targets between GLA and DbCM were identified and found to be significantly enriched in the AMPK, PI3K-Akt, Ras, Relaxin, Rap1, AGE-RAGE, Thyroid hormone, Sphingolipid, cAMP, and HIF-1 signaling pathways. The protective effects of GLA on HGHP-induced cytotoxicity, apoptosis, ferroptosis, and fibrosis were abolished following Ampk knockdown. Moreover, GLA mitigated myocardial ferroptosis and fibrosis in DbCM mouse models by activating the AMPK signaling pathway. Collectively, these findings demonstrate that GLA ameliorates DbCM by attenuating cardiomyocyte injury, ferroptosis, and fibrosis via activation of the AMPK signaling pathway, highlighting its potential as a therapeutic agent for DbCM.