Cinnamic Acid Attenuates Ethanol‐Exacerbated Hepatocyte Pyroptosis in Type 2 Diabetes via AMPK ‐Mediated NLRP3 / GSDMD Inhibition

Type 2 diabetes mellitus (T2DM) is frequently accompanied by chronic ethanol (ET) consumption, which worsens metabolic dysregulation and organ damage. Cinnamic acid (CA), a natural compound with anti-diabetic and hepatoprotective effects, shows therapeutic potential, but its role in mitigating ET-exacerbated hepatocyte injury in diabetes remains unclear. This study thus investigated whether CA protects against ET-induced hepatocyte pyroptosis under diabetic conditions and explored the underlying mechanisms. In vitro, HepG2 cells cultured under high-glucose (HG) conditions were exposed to ET to simulate a diabetic state with concomitant alcohol intake. Pyroptosis was evaluated by morphological examination and annexin V/PI staining. The involvement of the NACHT, LRR and PYD domains-containing protein 3 (NLRP3)/gasdermin D (GSDMD) pathway and AMP-activated protein kinase (AMPK) activation was assessed via immunoblotting, reactive oxygen species (ROS) detection, and molecular docking. In vivo, a T2DM mouse model was established using a high-fat diet combined with streptozotocin injection, followed by ET exposure and CA treatment. Metabolic parameters, histopathological changes, and hepatic signaling pathways were analyzed. Our results showed that ET exposure significantly increased pyroptotic body formation, ROS production, and NLRP3/GSDMD pathway activation in HG-treated HepG2 cells-all of which were reversed by CA in a concentration-dependent manner. Mechanistically, CA directly bound to and activated AMPK, and the protective effects were abolished by the AMPK inhibitor Compound C. In T2DM mice, ET exposure aggravated insulin resistance, dyslipidemia, hepatic steatosis, and histopathological abnormalities, whereas CA intervention ameliorated these adverse effects and modulated the AMPK-NLRP3/GSDMD signaling axis in liver tissue. Collectively, these findings demonstrate that CA alleviates ET-exacerbated hepatocyte pyroptosis under diabetic conditions by activating AMPK and subsequently inhibiting the NLRP3/GSDMD signaling cascade. This study provides novel insights into the therapeutic potential of CA in T2DM complicated by alcoholic hepatocellular injury.