Kynurenine monooxygenase blockade reduces endometriosis-like lesions, improves visceral hyperalgesia, and rescues mice from a negative behavioural phenotype in experimental endometriosis

Ben Higgins, Ioannis Simitsidellis, Xiaozhong Zheng, Frances Collins, Natalie Homer, Scott G Denham, Joanna Simpson, Mike Millar, Lyndsey Boswell, Hee Y Lee, Y Kim, Kyung Ho Park, Larry C. Park, Patrick J. Sweeney, Gerard Feraille, Alessandro Taddei, David Chagras, Thierry Alvarez, Scott P. Webster, Andrew W. Horne, Philippa T. K. Saunders, Damian J. Mole
In: eLife · 2024 · doi:10.7554/elife.99226 · W4401255971
preprint OA: gold CC0
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⚙ AI-generated summary by claude@2026-06, 2026-06-08 ⓘ

Kynurenine monooxygenase blockade with KNS898 reduced endometriosis lesions, improved pain behaviors, and mitigated negative behavioral phenotypes in a mouse model.

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⚙ AI-generated deep summary by claude@2026-06, 2026-06-09 ⓘ

This paper investigated whether the mitochondrial tryptophan-metabolism enzyme kynurenine monooxygenase (KMO) is expressed in endometriosis lesions and whether pharmacologic KMO blockade with the oral inhibitor KNS898 can reduce lesion burden and endometriosis-like pain behaviours in a mouse model. Using immunohistochemistry on biobanked human eutopic endometrium and peritoneal/ovarian lesions, the authors found KMO strongly expressed in lesion epithelial structures, and in mice, oral KNS898 produced measurable target engagement with increased kynurenine/added kynurenic acid and markedly reduced 3-hydroxykynurenine (3HK). In the experimental endometriosis model, KNS898 decreased the incidence and burden of distended endometrial gland-like structures and improved visceral hyperalgesia and negative behavioural phenotypes even when treatment started one week after lesion initiation, with no reported differences in lesion size metrics or body-weight effects between groups. This study is limited by small sample sizes for some dosing/metabolite measurements (e.g., n=3 per dose group). This paper is centrally about endometriosis — targeting KMO with KNS898 to reduce experimental endometriosis-like lesions and pain/behavioural outcomes.

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Abstract

Summary Endometriosis is a common and debilitating neuro-inflammatory disorder that is associated with chronic pain. Definitive diagnosis is based on the presence of endometrial-like tissue (lesions) in sites outside the uterus. Kynurenine monooxygenase (KMO) is a mitochondrial enzyme of tryptophan metabolism that regulates inflammation and immunity. Here, we show that KMO is expressed in epithelial cells in human endometriosis tissue lesions and in corresponding lesions in a mouse model of endometriosis. In mice, oral treatment with the potent KMO inhibitor KNS898 induced a biochemical state of KMO blockade with accumulation of kynurenine, diversion to kynurenic acid and ablation of 3-hydroxykynurenine production. In the mouse model of endometriosis, KMO inhibition improved histological outcomes and endometriosis pain-like behaviours, even when KNS898 treatment commenced one week after initiation of lesions. Taken together, these results suggest that KMO blockade is a promising new non-hormonal therapeutic modality for endometriosis.

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endometriosis

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