Abstract

Background Chronic inflammation plays a key role in colorectal carcinogenesis, where tumor-associated macrophages (TAMs) critically promote tumor progression. Metabolic reprogramming of TAMs, particularly through the modulation of fatty acid oxidation (FAO), represents a promising therapeutic strategy; however, effective agents remain to be identified. Although the natural compound dioscin exhibits anti-tumor properties, its ability to regulate TAM plasticity and metabolism in colitis-associated colorectal cancer (CAC) remains unclear. Methods A mouse model of CAC was established using azoxymethane/dextran sulfate sodium (AOM/DSS). Mice were treated with dioscin, and tumor development was monitored. Bone marrow-derived macrophages were polarized into TAMs, and the effects of dioscin on polarization and metabolism were evaluated by flow cytometry, immunohistochemistry, Seahorse analysis, and biochemical assays. Systemic macrophage depletion assay via clodronate liposomes validated the necessity of TAMs. Molecular docking, CETSA, and DARTS assays identified the direct target of dioscin. Pharmacological or genetic modulation of PPARγ confirmed mechanistic necessity. Results Dioscin significantly suppressed colorectal tumorigenesis in vivo. This efficacy was abolished upon macrophage depletion, confirming TAMs dependency. Dioscin modulated the TAMs polarization by primarily suppressing the M2 phenotype, leading to an increase in the M1/M2 ratio. Mechanistically, dioscin directly bound to PPARγ, suppressing its expression and downstream CPT1A-mediated FAO. Seahorse analysis revealed impaired spare respiratory capacity. Notably, while FAO inhibition coincided with increased lactate production, glycolytic flux and gene expression remained unaltered. Both pharmacological activation and genetic ablation of PPARγ abrogated dioscin-induced FAO inhibition and TAMs polarization. Conclusion Our study demonstrates that dioscin inhibits colorectal carcinogenesis by directly target