Deoxycholic Acid and Lipoteichoic Acid cooperatively drive macrophage M2/M1 polarization via TGR5/STAT3 and TLR2/NF-κB to fuel HCC progression in obesity.

Background: Obesity-related hepatocellular carcinoma (HCC) is associated with gut microbiota dysbiosis. However, the specific roles of key microbial metabolites, deoxycholic acid (DCA) and lipoteichoic acid (LTA), in modulating the immune microenvironment and promoting HCC progression are not fully understood. Aim: This study aimed to elucidate the synergistic effects and mechanisms of DCA and LTA in obesity-related HCC. Methods: An obesity-related HCC model was established in mice using a high-fat diet combined with diethylnitrosamine. In vitro, macrophage and HCC cell co-culture systems were utilized, along with gene knockdown approaches. Results: Combined DCA and LTA treatment synergistically exacerbated liver fibrosis and tumorigenesis in the mouse model. This was accompanied by suppressed expression of Cdkn1a and Cdkn2a, and activation of GPC-3 and CD44. Mechanistically, DCA promoted M2 macrophage polarization via the TGR5-STAT3 axis, whereas LTA drove M1 polarization via TLR2-NF-κB. In co-culture, knockdown of TLR2 and TGR5 reversed the pro-tumorigenic effects of DCA and LTA, inhibiting the epithelial-mesenchymal transition and reducing cancer cell invasion. Conclusion: DCA and LTA synergistically promote HCC progression in obesity by co-modulating the TLR2-TGR5 signaling axis in macrophages, thereby reshaping the tumor immune microenvironment.