Abstract

Abstract Background Sepsis‐induced acute kidney injury (S‐AKI) is a major global public health concern, yet effective therapeutic strategies remain limited. Mitochondrial dysfunction in renal tissues is a key pathogenic mechanism underlying S‐AKI. GTS‐21, a selective α7 nicotinic acetylcholine receptor (α7nAChR) agonist, exhibits anti‐inflammatory and renoprotective effects in S‐AKI. Methods We investigated the role of α7nAChR in S‐AKI using both in vitro (lipopolysaccharide (LPS)‐induced renal tubular cell injury) and in vivo (caecal ligation and puncture (CLP)‐induced septic mice) models, with GTS‐21 treatment. Results GTS‐21 significantly attenuated mitochondrial dysfunction, suppressed apoptosis, and alleviated inflammation, thereby protecting renal tubular cells and renal tissues against LPS‐ and CLP‐induced injury. Mechanistically, GTS‐21 activated α7nAChR and upregulated myocyte enhancer factor 2 (MEF2), peroxisome proliferator‐activated receptor gamma coactivator 1‐alpha (PGC‐1α), and heme oxygenase‐1 (HO‐1), which collectively mediate its anti‐oxidative, anti‐apoptotic and anti‐inflammatory effects. Conclusion These findings suggest that GTS‐21 may represent a potential therapeutic strategy for sepsis‐induced kidney injury.