2. Academic Validation
  3. SLC25A39 regulates Hedgehog signaling to promote tumor progression and sorafenib resistance in hepatocellular carcinoma

SLC25A39 regulates Hedgehog signaling to promote tumor progression and sorafenib resistance in hepatocellular carcinoma

  • Sci Rep. 2025 Oct 15;15(1):36061. doi: 10.1038/s41598-025-20008-7.
Qian Qiu 1 2,  Hehe Yin 1 2,  Lulu Zhang 1 2,  Wen Xu 1 2,  Shiwei Zhu 1 2,  Qianqian Zhang 1 2,  Mengqi Zhao 1 2,  Yuting Qian 1 2,  Yatong Ruan 1 2,  Hui Zhang 1 2,  Zihao Wu 3 4,  Jiatao Liu 5,  Jing Ke 1,  Ying Dai 6,  Wei Wang 1,  Weijie Sun 7,  Yufeng Gao 8 9,  Honghai Xu 10 11
Affiliations

Affiliations

  • 1 Department of Pathology, the First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China.
  • 2 Innovation and Entrepreneurship Laboratory for College Students, Anhui Medical University, Hefei, 230032, China.
  • 3 Department of Geriatrics, Division of Life Sciences and Medicine, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei, 230002, China.
  • 4 Anhui Key Laboratory of Geriatric Immunology and Nutrition Therapy, Hefei, 230027, China.
  • 5 Department of Pharmacy, the First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui Province, China.
  • 6 Medical Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China.
  • 7 Department of Medical Oncology, First Affiliated Hospital of Bengbu Medical University, Bengbu, 233099, China. swj950128@163.com.
  • 8 Department of Infectious Diseases, the First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China. aygyf@126.com.
  • 9 Anhui Province Key Laboratory of Infectious Diseases, Anhui Medical University, Hefei, 230022, China. aygyf@126.com.
  • 10 Department of Pathology, the First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China. xuhonghai@ahmu.edu.cn.
  • 11 Innovation and Entrepreneurship Laboratory for College Students, Anhui Medical University, Hefei, 230032, China. xuhonghai@ahmu.edu.cn.
PMID: 41093994 DOI: 10.1038/s41598-025-20008-7
Abstract

Sorafenib is the standard treatment for advanced hepatocellular carcinoma (HCC), yet resistance limits its efficacy. The Hedgehog (HH) signaling pathway contributes to drug resistance by maintaining HCC stem cell characteristics, but its role at the single-cell level is underexplored. Utilizing single-cell RNA Sequencing (scRNA-seq) and machine learning, we identified solute carrier family 25 member 39 (SLC25A39) as a key regulator of the HH pathway. Analyses of various cohorts revealed that elevated SLC25A39 correlates with poor prognosis in HCC patients. SLC25A39 knockdown inhibited Cancer stem cell characteristics and reduced sorafenib resistance in vitro. Furthermore, combined SLC25A39 suppression and sorafenib treatment significantly hindered HCC progression in both in vitro and in vivo models. These findings highlight the potential of shSLC25A39 to enhance sorafenib sensitivity , presenting a new avenue for combating drug resistance and enhancing therapeutic effectiveness.

Keywords

Acquired resistance; HCC; Hedgehog signaling pathway; SLC25A39; ScRNA-seq; Sorafenib.

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