What question did this study set out to answer?

This research aims to explore the role of TLR4 in endometriosis and evaluate the effects of TLR4 inhibition on disease progression.

May 9, 2026Open Access

Targeting TLR4 Attenuates Endometriosis Progression by Suppressing NF-κB/NLRP3 Inflammasome Activation and Angiogenesis

Key Points

This research aims to explore the role of TLR4 in endometriosis and evaluate the effects of TLR4 inhibition on disease progression.
Collected ectopic endometriotic tissues and peritoneal fluid from 30 subjects (15 patients and 15 controls).
Utilized LPS and ATP stimulation on an endometriotic cell line and treated with TLR4 inhibitor TAK-242.
Established a murine endometriosis model to assess the effects of TLR4 deletion and TAK-242 on lesion growth and inflammation.
Ectopic endometriotic tissues exhibited significantly elevated TLR4/NF-κB/NLRP3/IL-1β signaling compared to controls (p < 0.05).
TAK-242 treatment significantly reduced inflammation markers including IL-1β and enhanced lesion weight reduction (p < 0.05).
TLR4 inhibition led to decreased PCNA proliferation and CD31 microvessel density, both indicating reduced angiogenesis (p < 0.05).

Abstract

Endometriosis is a chronic inflammatory disorder affecting approximately 10% of reproductive-age women, yet non-hormonal therapeutic options remain limited. This study investigates the role of the TLR4/NF-κB/NLRP3 inflammasome axis in endometriosis pathogenesis and evaluates the therapeutic potential of pharmacologic TLR4 inhibition. Ectopic endometriotic tissues, eutopic endometrium, and peritoneal fluid were collected from 15 patients with ovarian endometriosis and 15 control subjects. The endometriotic epithelial cell line 11Z was stimulated with LPS and ATP with or without the TLR4 inhibitor TAK-242. A murine endometriosis model was established in wild-type C57BL/6 and TLR4−/− mice treated with TAK-242. Expression of TLR4, p-p65, NLRP3, caspase-1, cleaved caspase-1 (p20), GSDMD-N, IL-1β, PCNA, and CD31 was assessed by qPCR, Western blot, IHC, and ELISA. Ectopic lesions showed significantly elevated TLR4/NF-κB/NLRP3/IL-1β signaling compared with eutopic and control endometrium (all p < 0.05). Peritoneal fluid IL-1β was increased in patients, indicating a localized pelvic inflammatory response. In vitro, TAK-242 suppressed LPS/ATP-induced NF-κB/NLRP3 activation, pyroptosis, and IL-1β secretion (p < 0.05). Furthermore, the NLRP3-specific inhibitor MCC950 confirmed the essential role of NLRP3 inflammasome activation in IL-1β maturation. In vivo, TLR4 deletion or TAK-242 treatment reduced lesion weight, PCNA proliferation, and CD31 microvessel density (all p < 0.05). TLR4 inhibition blocks NF-κB nuclear translocation and subsequent inflammasome activation, suggesting a potential role in attenuating inflammation and angiogenesis. The TLR4/NF-κB/NLRP3 axis may drive endometriosis progression by linking innate immunity, inflammasome activation, pyroptosis, with possible involvement in angiogenesis warranting further investigation. Pharmacological inhibition of TLR4 attenuates lesion growth, supporting TLR4 as a promising non-hormonal therapeutic target for endometriosis.

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