GAMG alleviates silicosis inflammation and fibrosis by targeting STING

Silicosis is a severe occupational lung disease characterized by persistent inflammation and progressive fibrosis with no effective treatment. Glycyrrhetinic acid-3-O-β-D-glucuronide (GAMG), an active metabolite of glycyrrhizin, has anti-inflammatory and anti-fibrotic efficacy in our previous work, but its direct molecular target remains unknown. Through integrated multi-omics and molecular docking, we identified stimulator of interferon genes (STING) as a key pathogenic driver and a potential target of GAMG in silica-induced pulmonary injury. In silicosis patients, levels of dsDNA, STING, HMGB1, and α-SMA were significantly elevated (P < 0.01) and correlated with disease severity. Surface plasmon resonance (SPR) showed that GAMG directly binds to STING (K_d = 11.44 µM). Cellular thermal shift assays (CETSA) further demonstrated that GAMG enhances STING stability. In MH-S macrophages, GAMG inhibited the STING/TBK1/NF-κB pathway and reduced silica-induced release of pro-inflammatory (IL-6 and TNF-α) and pro-fibrotic cytokine TGF-β1. In a murine silicosis model, GAMG (100 mg/kg) treatment reduced dsDNA accumulation and blocked STING activation. Moreover, GAMG alleviated lung inflammation and collagen deposition. Collectively, these findings revealed that GAMG targeted the STING/TBK1/NF-κB pathway to alleviate silicosis, identifying STING as a potential therapeutic target. This work supported GAMG as a promising natural metabolite for treating silica-induced lung injury.