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.