Irigenin Modulates BL‐Induced Pyroptosis in Retinal Pigment Epithelial Cells Through p38 MAPK and NFκB Pathways

Age-related macular degeneration (AMD), a primary cause of vision loss among older adults, is strongly associated with inflammatory processes. The current study aimed to elucidate the protective effects of irigenin, an isoflavonoid recognized for its anti-inflammatory, antioxidative, antiapoptotic, and anticancer activities, against blue light (BL)-induced damage in N-retinyl-N-retinylidene ethanolamine (A2E)-laden human adult retinal pigment epithelial (A2E-laden ARPE-19) cells. Pretreatment with irigenin markedly mitigated BL-induced cytotoxicity and preserved epithelial barrier function in a concentration-dependent manner. Moreover, irigenin significantly inhibited the expression of proinflammatory cytokines and activation of the nod-like receptor pyrin domain-containing 3 (NLRP3) inflammasome, as evidenced by decreased expression of NLRP3, ASC, and both full-length and cleaved forms of gasdermin D (GSDMD), along with reduced caspase-1 activity. Further mechanistic analyses indicated that irigenin effectively suppressed the activation of the nuclear factor kappa B (NFκB) signaling pathway, as evidenced by phosphorylation of NFκB and inhibitor of NFκB (IκB)α, and both activation and translocation of NFκB, along with reduced phosphorylation of p38 mitogen-activated protein kinase (MAPK). These findings underscore the potential of irigenin to ameliorate BL-induced retinal pigment epithelial cell damage via modulation of inflammation and pyroptosis pathways, suggesting its therapeutic value for preventing AMD.