Myocardial ischemia-reperfusion injury (MIRI) is a key factor affecting the prognosis of myocardial infarction patients. Currently, there remains a lack of specific drugs targeting MIRI, and it is unclear whether Piceatannol-3'-O-β-D-glucopyranoside (PG) improves MIRI through metabolic reprogramming. Therefore, this study takes a clinically oriented approach, using multi-omics technologies to investigate how PG regulates metabolic reprogramming to improve MIRI. The study focuses particularly on PG's regulation of lactate and lactylation. Results indicate that PG enhances LVEF and LVFS, reduces cTnI and CK-MB levels, decreases ROS, lactate, and LDH levels, and increases ATP expression, thereby improving cardiac function. Metabolomics results based on clinical serum samples indicate that PG can reduce lactate and pyruvate levels. The results of research conducted on animal subjects suggest that exogenous lactate supplementation has the capacity to attenuate the cardioprotective effects of PG. PG intervention significantly suppressed the expression of PDK4, MCT1, and ACSL4 proteins while enhancing GPX4 protein expression, inhibiting lipid peroxidation, and improving mitochondrial structure and function. However, the overexpression of PDK4 led to a diminution of the PG-mediated enhancement in MIRI. Overexpression of NDUFS1 K170 lactylation similarly impaired the PG-mediated improvement of MIRI. Therefore, we conclude that PG improves MIRI by inhibiting NDUFS1 K170 lactylation through metabolic reprogramming regulation. The present study provides novel targets and therapeutic agents for MIRI intervention, while also offering fresh insights into the pathogenesis of MIRI. • Silent PDK4 reduces lactate accumulation, thereby improving MIRI. • Inhibiting NDUFS1 K170 lactylation is an effective therapeutic approach for improving MIRI. • PG improves MIRI by inhibiting NDUFS1 K170 lactylation through metabolic reprogramming regulation
Fan et al. (Fri,) studied this question.