Propionate Ameliorates Endometriosis With Modulation of NLRP3 ‐Related Pyroptosis and Th17/Treg Balance

Danli Sun, Mi Gong
In: Comprehensive Physiology · 2026 · vol. 16(4) · doi:10.1002/cph4.70224 · W7202348509
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Propionate ameliorates endometriosis in rat models and macrophage cultures by suppressing NLRP3-related pyroptosis and restoring Th17/Treg immune balance, indicating its potential as a metabolic-immune therapeutic strategy.

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Abstract

ABSTRACT Objective To investigate the therapeutic effects of short‐chain fatty acids (SCFAs) in endometriosis (EMs) and determine whether these effects are associated with NLRP3‐related macrophage pyroptosis and immune regulation. Methods Integrated GEO datasets were analyzed to identify pyroptosis‐ and metabolism‐related pathways. Network pharmacology and molecular docking were used as hypothesis‐generating approaches to prioritize candidate targets. An autologous rat model of EMs was established to evaluate the effects of acetate, propionate, and butyrate on lesion growth, inflammation, intestinal barrier integrity, Th17/Treg balance, and pyroptosis‐related proteins. Propionate was further investigated using an LPS+ATP‐induced THP‐1 macrophage model, together with GBP5 expression analysis, NLRP3 overexpression rescue, and comparison with the NLRP3 inhibitor MCC950. Results Bioinformatics analyses suggested activation of pyroptosis‐related pathways and metabolic dysregulation in EMs. Rats with EMs exhibited reduced SCFA levels and impaired intestinal barrier‐related protein expression. Propionate and butyrate suppressed lesion growth, while propionate consistently reduced inflammatory cytokines, restored Th17/Treg balance, and decreased NLRP3, ASC, cleaved caspase‐1, GSDMD‐N, IL‐1β, and IL‐18 expression. In vitro, propionate attenuated LPS+ATP‐induced GBP5 expression and macrophage pyroptosis, whereas NLRP3 overexpression partially reversed these effects. MCC950 produced comparable inhibitory effects, and combination treatment further enhanced the response. Molecular docking generated preliminary structural hypotheses but did not demonstrate direct target binding. Conclusion SCFA metabolic dysregulation is associated with EMs. Propionate supplementation attenuates inflammation, improves immune homeostasis, and suppresses NLRP3‐related macrophage pyroptosis, highlighting metabolic‐immune regulation as a potential therapeutic strategy for endometriosis.

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