18β‐Glycyrrhetinic Acid and a Nano‐Liposomal Formulation Alleviate Depression‐Like Behaviors via the Microglial mTOR‐Autophagy‐NLRP3 Axis

ABSTRACT The limited efficacy and slow onset of current antidepressants underscore the urgent need for novel therapeutic strategies. Here, we established a novel zebrafish inflammation‐based screening model and identified 18β‐glycyrrhetinic acid (18β‐GA) as a potent anti‐inflammatory candidate. In a chronic social defeat stress (CSDS) mouse model, 18β‐GA demonstrated significant antidepressant effects, which were associated with attenuated neuroinflammation and a shift in microglial polarization toward an anti‐inflammatory phenotype. Mechanistically, 18β‐GA inhibited the mTOR/p70S6K signaling pathway, leading to the restoration of autophagy and subsequent suppression of NLRP3 inflammasome activation in microglia. Using a transwell co‐culture system, we further confirmed that 18β‐GA protects neurons from microglia‐mediated inflammatory injury. To overcome pharmacokinetic limitations, we developed a nanoliposomal formulation (Nano 18β‐GA) that achieved rapid brain accumulation within 0.5 h, as visualized by time‐dependent in vivo imaging. Remarkably, a single administration of Nano 18β‐GA produced significant antidepressant effects, maintained the original mechanism of action, and exhibited a favorable biosafety profile. Together, our work delineates a translational pipeline from natural product discovery to nano‐enabled therapy, offering a rapidly acting strategy with substantial translational potential for depressive disorder.