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

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

  • Int J Biol Macromol. 2025 Oct 9;330(Pt 3):148223. doi: 10.1016/j.ijbiomac.2025.148223.
Xiaopei Peng 1,  Zhenhu He 1,  Dandan Yuan 2,  Jiong Li 1,  Yaning Zhu 1,  Xuan Zhang 1,  Huaping Liu 3,  Mengtian Ma 4,  Juan Wang 5,  Zhenguo Liu 5,  Xiaolong Qi 6,  Pengfei Rong 7
Affiliations

Affiliations

  • 1 Department of Radiology, the Third Xiangya Hospital, Central South University, Changsha, 410013, China.
  • 2 Department of Radiology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China.
  • 3 Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University/Hunan Cancer Hospital, Changsha, 410013, China.
  • 4 Department of Radiology, The First Hospital of Hunan University of Chinese Medicine, Changsha, 410013, China.
  • 5 Department of Infectious Disease, The Third Xiangya Hospital, Central South University, Changsha, 410013, China.
  • 6 Department of Radiology, Zhongda Hospital, Southeast University, Nanjing, 210000, China.
  • 7 Department of Radiology, the Third Xiangya Hospital, Central South University, Changsha, 410013, China. Electronic address: rongpengfei66@csu.edu.cn.
PMID: 41075888 DOI: 10.1016/j.ijbiomac.2025.148223
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.

Keywords

Hepatocellular carcinoma; Macrophage; SLC16A3; Sorafenib resistance; Tumour microenvironment.

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