ABSTRACT Objective This study aims to screen potential targets of Curcumin (Cur) in Myocardial ischaemia–reperfusion injury (MIRI) using network pharmacology and molecular docking, and to experimentally validate whether Cur mitigates MIRI by modulating the NLRP3 inflammasome and pyroptosis via the Nrf2/HO‐1 pathway. Methods Potential Cur–MIRI targets were identified from public databases and analysed by topological algorithms; molecular docking assessed binding affinity. Cardioprotective effects were validated in vivo using a murine LAD ligation model (30 min ischaemia/24 h reperfusion) and in vitro using H9C2 cardiomyocytes subjected to hypoxia/reoxygenation (H/R). Cur was given as pretreatment. Mechanistic assays included tissue immunofluorescence, mtROS and JC‐1 staining, ELISA for cytokines, and Western blotting; Nrf2 was silenced by siRNA to test dependency. Results Network analysis revealed 481 common targets enriched in apoptosis, TNF and NOD‐like receptor pathways. Docking showed favourable binding to NLRP3 (−8.14 kcal/mol) and Nrf2 (−7.02 kcal/mol). In vivo Cur reduced myocardial injury markers, improved echocardiographic function, attenuated inflammation and mitochondrial ultrastructural damage, and decreased NLRP3/caspase‐1 expression. In vitro Cur lowered IL‐1β/IL‐18 and mtROS, preserved mitochondrial membrane potential, reduced apoptosis, upregulated Nrf2/HO‐1 and downregulated pyroptosis proteins (NLRP3, ASC, caspase‐1, GSDMD). Nrf2 silencing abolished these effects. Conclusion Combining in silico and experimental evidence, Cur attenuates MIRI by activating Nrf2/HO‐1 to inhibit NLRP3 inflammasome‐mediated pyroptosis.
Yao et al. (Thu,) studied this question.