Amlexanox alleviates renal inflammation and fibrosis by inhibiting cGAS/STING/TBK1 and TGF-β1/Smad signaling.

BACKGROUND

The cGAS/STING/TBK1 signaling is a key regulator of the renal innate immune response, driving sterile inflammation and fibrosis. This study explores the therapeutic efficacy of amlexanox (AMX), a TANK-binding kinase 1 (TBK1) inhibitor, in attenuating renal inflammation and fibrosis.

METHODS

Normal rat kidney fibroblast (NRK-49F) cells were induced with transforming growth factor-β1 (TGF-β1) to evaluate myofibroblast transition. Renal inflammation and fibrosis were induced in mice via unilateral ureteral obstruction (UUO), followed by oral administration of AMX at 3, 10, and 30 mg/kg doses. Renal injury and extracellular matrix (ECM) remodeling were evaluated through histopathology and immunohistochemistry. To elucidate the underlying molecular mechanisms, immunoblotting and immunofluorescence were performed.

RESULTS

AMX attenuated TGF-β1-induced Smad phosphorylation, thereby suppressing myofibroblast activation and the subsequent overexpression of fibronectin and collagen I. In vivo, AMX reduced oxidative stress, ameliorated histopathological renal damage, and improved kidney function. Mechanistically, AMX downregulated the expression of cyclic GMP-AMP synthase (cGAS), stimulator of interferon genes (STING), pSTING, and pTBK1, thereby inhibiting nuclear factor kappa B (NF-κB)-dependent transcription of pro-inflammatory mediators and interferon regulatory factor (IRF3)-mediated type I interferon (IFN) response. Furthermore, AMX attenuated ECM remodeling by modulating the TGF-β1/Smad pathway.

CONCLUSION

AMX exerts renoprotective effects by targeting both inflammation and fibrosis through the inhibition of the cGAS/STING/TBK1 and TGF-β1/Smad signaling pathway.