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

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.