Targeting Inflammasome-mediated Tumor Progression in Colon Adenocarcinoma: Integrative In silico Analysis for Metformin Repurposing
Abstract
Abstract Background: Colon adenocarcinoma (COAD) is the most prevalent type of colorectal cancer, originating from glandular cells lining the colon. This study investigated the expression and functional relevance of inflammasome-associated genes (NOD-like receptor family pyrin domain containing 3 [NLRP3], caspase-1 [CASP1], interleukin-1 beta [IL-1 β], and interleukin-18 [IL-18]) in COAD and explored metformin as a repurposed inflammasome modulator. Methods: An integrative in silico approach was employed to analyze the expression, survival significance, and stage specific expression in COAD. Metformin was evaluated through target prediction, absorption, distribution, metabolism, excretion, and toxicity profiling, molecular docking, and 100 ns molecular dynamics (MD) simulations to assess its interaction with inflammasome-associated proteins. Results: Analysis revealed that all four genes are significantly upregulated in COAD. High expression of NLRP3 and IL-1 β strongly predicts poor overall survival and correlates with advanced disease stage, suggesting a pro-tumorigenic role for chronic inflammasome activation in established COAD. While CASP1 was upregulated, its expression level was not prognostic, indicating upstream NLRP3 activation and IL-1 β effector levels are rate-limiting. Metformin was identified as a promising inhibitor with an excellent safety profile. Molecular docking demonstrated strong binding affinities with Pro-caspase, NLRP3, and IL-1 β as key targets.…
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