Abstract

Licorice, a widely used herb in food additives and nutraceuticals, primarily exerts its biological effects through 18β-glycyrrhetinic acid (18β-GA) in vivo. Here, we aimed to investigate whether 18β-GA attenuates obesity-associated white adipose tissue (WAT) inflammaging and to clarify the molecular events responsible for its protective effects. Using a high-fat diet mouse model together with cultured adipose progenitor cells (APCs), we found that 18β-GA significantly mitigated inflammation and cellular senescence in WAT, diminished the expression of senescence-associated secretory phenotype (SASP), and restored APC adipogenic differentiation potential. Network pharmacology analysis pinpointed HMGCR (3-hydroxy-3-methylglutaryl-CoA reductase) as a key candidate target, with subsequent experiments confirming that the anti-inflammaging effect of 18β-GA was comparable to established HMGCR inhibitors. Furthermore, 18β-GA markedly reduced cholesterol accumulation in WAT, which directly induces APC senescence, suggesting that cholesterol homeostasis regulation represents a key mechanism responsible for its protective activity. Thus, 18β-GA emerges as a promising nutraceutical agent for combating obesity-driven metabolic disorders and chronic inflammation in WAT.