Targeting Inflammasome-mediated Tumor Progression in Colon Adenocarcinoma: Integrative In silico Analysis for Metformin Repurposing
Sangeetha Raja, Jamuna RaniAbstract
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
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. Subsequent 100 ns MD simulations showed that while the IL-1 β-Metformin complex was moderately stable, the IL-18-Metformin complex exhibited greater stability and more persistent key interactions.
Conclusions:
In conclusion, these computational findings identify the NLRP3 inflammasome as a critical prognostic pathway in COAD and provide a strong mechanistic rationale for validating metformin as a therapeutic modulator of this axis.