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

## TL;DR

Irigenin protects retinal cells from blue light damage by reducing inflammation and cell death, offering potential for AMD prevention.

## Contribution

Irigenin's novel protective mechanism against blue light-induced retinal damage via p38 MAPK and NFκB pathways is demonstrated.

## Key findings

- Irigenin reduces blue light-induced cytotoxicity and preserves epithelial barrier function.
- Irigenin inhibits NLRP3 inflammasome activation and proinflammatory cytokine expression.
- Irigenin suppresses NFκB and p38 MAPK signaling pathways.

## Abstract

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.

Irigenin alleviates blue light‐induced RPE cell damage by inhibiting NLRP3 inflammasome and p38/NF‐κB signalling, showing potential for AMD prevention.