Chebulagic Acid Activates the STON2-TFEB Axis to Promote Lysosomal Biogenesis to Inhibit NLRP3-Mediated Inflammasome

Abstract

Lysosomal biogenesis is the coordinated process by which cells generate and maintain lysosomes, the acidic organelles responsible for degrading macromolecules, sensing nutrients, and maintaining cellular homeostasis The lysosome acts as a signaling hub for mTOR TFEB Additionally, the lysosome's primary function is to facilitate autophagy, which is essential for cellular degradation and maintenance of cellular homeostasis To regulate lysosomal biogenesis along with targeting mTOR, autophagy, and the inflammasome axis, we used Terminalia bellirica derived bioactive compounds for therapeutic applications Chebulagic acid is a hydrolysable tannin derived from Terminalia bellirica, which is used for our study However, its mechanistic role in lysosomal dynamics and inflammasome regulation remains largely unexplored Our findings demonstrate that chebulagic acid promotes lysosomal biogenesis by activating the STON 2 TFEB signaling axis, accompanied by enhanced expression of autophagy markers ATG 5 BECN 1 and LC 3 as well as reduced levels of the autophagy related protein p 62 In parallel, chebulagic acid attenuated mTOR activity by disrupting its lysosomal membrane localization, thereby facilitating sustained induction of autophagy For the therapeutic evaluation of chebulagic acid, we examined its anti inflammatory potential using arecoline as a positive control for NLRP 3 mediated inflammasome activation Treatment with chebulagic acid markedly reduced the expression of the NLRP 3 signaling axis, thereby limiting inflammasome driven inflammatory responses Interestingly, NRF 2 expression was also reduced, indicating that NRF 2 is not directly involved in chebulagic acid mediated regulation of the NLRP 3 inflammasome Instead, our results suggest that the observed decrease in NLRP 3 levels is a consequence of autophagy mediated degradation Taken together, these findings highlight the multi targeted actions of chebulagic acid, which enhance lysosomal biogenesis, suppress mTOR activity, and promote autophagic clearance of NLRP 3 ultimately attenuating inflammasome activation.