18β-glycyrrhetinic acid mitigates lipotoxicity-induced premature senescence of tubular epithelial cells by activating SIRT1-TFEB signaling

BACKGROUND: Targeting metabolic disorders has emerged as a promising therapeutic strategy in the treatment of chronic kidney disease (CKD). 18β-glycyrrhetinic acid (18β-GA) is known for its metabolic regulatory and antioxidant effects in various diseases. However, the precise effects and underlying mechanisms of 18β-GA on CKD remain unclear. PURPOSE: This study aims to evaluate the therapeutic efficacy of 18β-GA on CKD and to identify the molecular targets of 18β-GA with a particular emphasis on its role in metabolic regulation. STUDY DESIGN AND METHODS: A high-fat diet-induced CKD model was established to investigate the influence of 18β-GA on lipid metabolic disorders, cellular senescence and fibrosis in the kidneys. Co-immunoprecipitation was performed to investigate the impact of 18β-GA on the interaction between transcription factor EB (TFEB) and sirtuin 1 (SIRT1). Additionally, network pharmacology and molecular docking analyses were conducted to identify the specific target proteins of 18β-GA. RESULTS: 18β-GA alleviated renal lipid accumulation, tubular cell senescence and renal interstitial fibrosis in CKD mice. Treatment with 18β-GA largely restored mitochondrial function and attenuated intracellular lipotoxicity and associated cellular senescence by promoting lipophagy in renal tubular cells. Mechanistically, 18β-GA acting as a partial antagonist of peroxisome proliferator-activated receptor gamma (PPARγ) enhanced lipophagy through SIRT1-mediated nuclear translocation of TFEB which induced the expression of microtubule-associated protein light chain 3 (LC3). CONCLUSION: Our findings demonstrate that 18β-GA, functioning as a partial antagonist of PPARγ, counteracts CKD progression by activating the SIRT1-TFEB-LC3 signaling axis-mediated lipophagy and thus uncover a novel mechanism by which 18β-GA improves renal lipid metabolism disorders and exerts renoprotective effects. These results highlight the potential of 18β-GA as a promising therapeutic agent for the treatment and prevention of CKD.