Curcumin Alleviates Myocardial Ischaemia–Reperfusion Injury by Inhibiting NLRP3 Inflammasome Activation and Pyroptosis via the Nrf2/HO‐1 Pathway: An Integrated Network Pharmacology and Experimental Study

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.