Work

The role of solute carrier family 16 member 3 protein in hepatocellular carcinoma and sorafenib resistance

Year: 2025

Type: article

Abstract: Solute carrier family 16 member 3 (SLC16A3), a key protein mediating lactic acid efflux, promotes immune evasion and angiogenesis in tumour, correlating with poor prognosis and potentially impairing anti-angiogenic therapies like sorafenib. To elucidate SLC16A3's role and mechanism in hepatocellular carcinoma (HCC), particularly concerning sorafenib, we analysed public datasets and employed molecular biology techniques, animal experiments, and transcriptome sequencing. Our findings revealed that elevated SLC16A3 protein expression correlates with poor prognosis, reduced sorafenib response, and an altered tumour immune microenvironment (TIME), characterized by suppressed macrophage polarization. Mechanistically, sorafenib itself upregulates SLC16A3 protein expression by enhancing glycolysis, increasing lactate secretion which fosters an immunosuppressive TIME. Conversely, SLC16A3 inhibition promoted M1 macrophage polarization and CD8 + T cell infiltration, thereby enhancing sorafenib efficacy. Transcriptomic analysis demonstrated that SLC16A3 overexpression selectively downregulates cytokine signalling (reducing CCL5, CCL9, CXCL10) while upregulating CCL8, revealing how this protein contributes to immunosuppression. These findings broaden our understanding of SLC16A3 protein's role in HCC prognosis and sorafenib resistance, indicating that combining SLC16A3 inhibition with sorafenib represents a promising therapeutic strategy.

Source: International Journal of Biological Macromolecules

DOI: 10.1016/j.ijbiomac.2025.148223