Lycium Barbarum Polysaccharide Antagonizes Cardiomyocyte Pyroptosis by Inhibiting the Nrf2/NLRP3 Signal Pathway Against Myocardial Ischemia–Reperfusion Injury

, has garnered considerable attention in the prevention and treatment of cardiovascular diseases due to its anti-inflammatory, antioxidant, vasomotor function-improving, and antithrombotic properties. This study aims to investigate the ability of LBP to alleviate MIRI, with a specific focus on its role in modulating the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome. Myocardial ischemia/reperfusion (I/R) models in rats and hypoxia/reoxygenation (H/R) models in H9c2 cells were established. Myocardial injury and the therapeutic effect of LBP were evaluated by 2,3,5-Triphenyl tetrazolium chloride (TTC) staining, Hematoxylin-eosin (H&E) staining, Terminal deoxynucleotidyl transferase dUTP Nick-End Labeling (TUNEL) staining, and Enzyme-linked immunosorbent assay (ELISA). To elucidate the specific mechanism underlying LBP against MIRI, an Nrf2-overexpressing cell line was generated in H9c2 cells, and pharmacological inhibition of Nrf2 with ML385 was applied for complementary validation. The effects of LBP on H/R-induced oxidative stress, inflammatory response (IL-18, IL-1β), and pyroptosis-related protein expression (NLRP3, apoptosis associated speck-like protein containing a CARD (ASC), cysteine-dependent aspartate-specific proteases (caspase)-1, Gasdermin D (GSDMD)) were systematically evaluated. LBP administration conferred robust cardioprotection in I/R rats, as evidenced by a significant reduction in myocardial infarct size, improved preservation of myocardial fiber architecture, and attenuated leakage of cardiac injury biomarkers (lactate dehydrogenase (LDH) and creatine kinase-MB (CK-MB)). Mirroring these in vivo findings, LBP pretreatment effectively shielded H9c2 cardiomyocytes from H/R insult, markedly enhancing cell viability while curtailing reactive oxygen species (ROS) accumulation and apoptotic activation. A pivotal finding was the pronounced downregulation of Nrf2 in the H/R group, a deficit that was conclusively reversed by LBP treatment. To decisively establish a causal role for Nrf2, we employed a loss-of-function approach; Nrf2 inhibition completely abrogated the protective benefits of LBP, culminating in exacerbated tissue damage, a surge in ROS, and the upregulation of key pyroptosis effectors (NLRP3, ASC, caspase-1, GSDMD). Conversely, a complementary gain-of-function experiment demonstrated that Nrf2 overexpression alone was sufficient to mimic LBP's effects, significantly blunting H/R-induced ROS production and pyroptosis. LBP alleviates MIRI by inhibiting pyroptosis through activating the Nrf2/NLRP3 axis, thus representing a promising therapeutic candidate for ischemic heart disease with the potential to improve patient outcomes.