ArticleFrontiers in immunology2026
ANGPT1-GABARAP axis modulates NLRP3 inflammasome-mediated pyroptosis in Crohn's disease.
Article in Frontiers in immunology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Background: Crohn Methods: Protein quantitative trait locus (pQTL)-based two-sample Mendelian randomization (MR) was performed to prioritize pyroptosis-related proteins genetically associated with CD risk. Putative upstream regulators of GABARAP were then examined by two-step MR and mediation analysis. Functional validation was performed using a dextran sulfate sodium (DSS)-induced murine colitis model and LPS plus nigericin-induced cell models of NLRP3 inflammasome activation. ANGPT1-GABARAP signaling and the NLRP3-Caspase-1-GSDMD pathway were evaluated following GABARAP or ANGPT1 knockdown and exogenous recombinant human ANGPT1 (rhANGPT1) supplementation, by qRT-PCR, western blotting, ELISA, and LDH release assays. Results: MR analysis prioritized GABARAP as a suggestive protective candidate for CD, with genetically predicted higher GABARAP levels associated with a decreased disease risk (OR = 0.563, 95% CI 0.327-0.968, P = 0.038). Two-step MR further suggested a putative genetic association between ANGPT1 and GABARAP, and mediation analysis indicated that GABARAP may partially mediate the genetically predicted ANGPT1-CD association, with an estimated mediation proportion of 22.97%. DSS-induced colitis was associated with reduced ANGPT1 and GABARAP expression, along with increased NLRP3 expression, Caspase-1 processing, GSDMD-N accumulation, and elevated IL-1β, IL-18, and LDH levels. Conclusion: These findings support a potential role for the ANGPT1-GABARAP axis in NLRP3 inflammasome-mediated pyroptosis associated with intestinal inflammation. Together, these results provide a genetically informed framework for understanding pyroptosis-related inflammatory signaling in CD and support further investigation of the potential therapeutic relevance of this axis.
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