Liriodendrin alleviates endometriosis via PPARγ activation and inhibition of NLRP3 inflammasome-mediated pyroptosis.

BACKGROUND: Excessive activation of inflammatory responses and oxidative stress plays a critical role in the pathophysiology of endometriosis (EMs), which is characterized by ectopic lesion growth and chronic pelvic pain. However, effective non-hormonal therapies targeting these processes remain limited. PURPOSE: To investigate the inhibitory effects of Liriodendrin (LIR) on EMs progression and elucidate its underlying mechanisms. STUDY DESIGN: An integrative experimental study combining in vivo, in vitro, transcriptomic, and mechanistic analyses. METHODS: An EMs mouse model was established via intraperitoneal implantation of endometrial fragments. Lesion size, weight, histopathology, and pain-related markers were assessed. Transcriptomic profiling combined with LASSO regression and protein-protein interaction (PPI) network analysis was used to identify key targets. Cellular thermal shift assays (CETSA), SPR and molecular dynamics simulations were used to assess LIR-protein interactions. PPARγ knockdown, along with agonist and antagonist interventions, was performed to determine pathway dependence. Oxidative stress and pyroptosis were evaluated by measuring ROS levels, NRF2/HO-1 signaling, and pyroptosis-related markers (NLRP3, GSDMD, IL-1β, IL-18) using Western blot, RT-qPCR, and fluorescence staining. RESULTS: LIR significantly inhibited ectopic lesion growth and attenuated thermal hyperalgesia, accompanied by reduced expression of the nociceptive markers NGF, TRPV1, CGRP, and IB4. Mechanistically, LIR activated the PPARγ/RXRα/NRF2 antioxidant pathway and attenuation of oxidative stress. LIR suppressed NLRP3 inflammasome activation and GSDMD-mediated pyroptosis, accompanied by reduced secretion of IL-1β and IL-18. CONCLUSION: LIR alleviates EMs progression through modulation of PPARγ-associated antioxidant signaling and attenuation of NLRP3-associated pyroptotic activation, highlighting its potential as a non-hormonal therapeutic candidate.