Metformin Attenuates Myocardial Ischemia-Reperfusion Injury in Rats by Modulating JNK Pathway and Inhibiting PANoptosis Mechanisms.

Purpose: Myocardial ischemia-reperfusion injury (MIRI) is a condition in which the heart is aggravated when blood flow is restored after tissue damage caused by ischemia. Metformin (Met), a widely prescribed antidiabetic medication, has demonstrated promising cardioprotective properties, particularly through its anti-inflammatory, antiapoptotic, and metabolic regulatory mechanisms. This study investigates the cardioprotective effects of Met in a rat model of MIRI, focusing on its modulation of the c-Jun N-terminal kinase (JNK) pathway and inhibition of PANoptosis mechanisms. Methods: The proportion of myocardial infarction was determined by triphenyl tetrazole chloride (TTC) staining. Wheat germ agglutinin (WGA) staining is used to determine whether myocardial cells are hypertrophic and other pathological conditions. Serum markers of myocardial injury along with inflammatory cytokines were measured by enzyme-linked immunosorbent assay (ELISA). Immunofluorescence and Western blotting were employed to evaluate myocardial cell PANoptosis and the involvement of the JNK pathway. Results: After MIRI, TTC staining revealed apparent myocardial infarction, and WGA staining showed significant myocardial cell hypertrophy. There was also a marked increase in myocardial injury markers, inflammatory factors, and reactive oxygen species (ROS). Met significantly reduced the myocardial injury area and notably lowered serum levels of c-TnI, CK-MB, LDH, IL-6, TNF-α, and ROS. Immunofluorescence and Western blot analyses demonstrated that Met attenuates myocardial cell PANoptosis by inhibiting JNK phosphorylation and reducing ROS generation. The cardioprotective effect of Met was reversed by the addition of anisomycin (ANI). The protective effect of JNK-specific inhibitors administered as monotherapy was found to be comparable to that of Met. The aforementioned results suggest that the regulation of the JNK pathway is a critical factor contributing to its protective effect. Conclusion: The cardioprotective effect of Met in the rat model of MIRI is mediated through the regulation of the JNK pathway and PANoptosis. These findings suggest that Met may provide a potential therapeutic approach for treating MIRI.