Icariin ameliorates chronic renal failure and fibrotic injury by modulating the STING signaling pathway to promote mitophagy

Background Chronic renal failure (CRF) is characterized by progressive renal function decline, oxidative stress (OS), inflammation, and fibrosis, with a current lack of effective treatments. This study investigates the interventional effects of Epimedium extract (EPE) on CRF and focuses on the elucidation of its potential mechanisms of action. Methods In vivo and in vitro experiments were conducted using a CRF rat model and a TGF-β1-induced fibrosis model in human renal tubular epithelial cells (HK-2). Rats were randomly assigned to control, model, low/high-dose EPE, and EPE combined with Mdivi-1 experimental groups. HK-2 cells were grouped into control, TGF-β1, EPE-treated, and STING overexpression groups. Renal function parameters (SCR, BUN, UPR), OS markers (ROS, MDA, GSH, SOD), inflammatory cytokines (IL-1β, IL-6, TNF-α), fibrosis markers (Hyp, MMP2/9, α-SMA, Col-1, FN), autophagy-related proteins (LC3B, Beclin1, ATG5, p62), and key molecules of the cGAS-STING pathway were assessed to explore the protective effects and underlying mechanisms of EPE in CRF. Results EPE significantly improved renal function, reduced OS and inflammatory responses, alleviated pathological damage and fibrosis in renal tissues, and promoted the expression of autophagy-related proteins in CRF rats. Mdivi-1 partially reversed the protective effects of EPE, suggesting autophagy-dependent mechanisms. Mechanistically, EPE inhibited cGAS-STING pathway activation and reduced the phosphorylation of downstream TBK1 and IRF3. In HK-2 cells, EPE mitigated TGF-β1-induced apoptosis, OS, inflammation, and fibrosis, while promoting mitophagy. However, STING overexpression attenuated these protective effects. Conclusion EPE ameliorates renal dysfunction, OS, inflammation, and fibrosis in CRF by suppressing cGAS-STING signaling activation and enhancing autophagy activity. This study provides experimental evidence supporting EPE as a potential therapeutic agent for chronic kidney disease and highlights the regulatory role of the cGAS-STING pathway in renal fibrosis. Graphical abstract