SLC27A5 deficiency-induced reduction in long-chain fatty acid uptake is a pro-tumorigenic metabolic adaptation and confers sensitivity to glutaminase inhibition in hepatocellular carcinoma

  • Cancer Lett. 2026 Sep 1:655:218616. doi: 10.1016/j.canlet.2026.218616.
Xiaoyan He  1 ,  Zhengwei Zhao  2 ,  Teng Wei  3 ,  Lisi Zheng  2 ,  Jincui Yang  2 ,  Xinrong He  2 ,  Yicai Cheng  2 ,  Xiaoyi Zhan  2 ,  Zejuan Li  2 ,  Kelin Wu  2 ,  Stephanie Roessler  4 ,  Yunting Jian  5 ,  Chuli Fu  6 ,  Guang-Rong Yan  7 ,  Junyao Xu  8 ,  Qiangnu Zhang  9
Affiliations
  • 1. Department of Pathology, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China; Biomedicine Research Center, Guangdong Provincial Key Laboratory of Major Obstetric Disease, Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology, The Third Affiliated Hospital, Guangzhou Medical University, Guangzhou, 510623, China.
  • 2. Biomedicine Research Center, Guangdong Provincial Key Laboratory of Major Obstetric Disease, Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology, The Third Affiliated Hospital, Guangzhou Medical University, Guangzhou, 510623, China.
  • 3. School of Basic Medicine, Gannan Medical University, Ganzhou, Jiangxi, China.
  • 4. Institute of Pathology, Heidelberg University Hospital, Heidelberg, 69120, Germany.
  • 5. Department of Pathology, Guangdong Provincial Key Laboratory of Major Obstetric Disease, Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology, The Third Affiliated Hospital, Guangzhou Medical University, Guangzhou, 510150, China. Electronic address: [email protected].
  • 6. Department of Hematology and Oncology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, 510623, China. Electronic address: [email protected].
  • 7. Biomedicine Research Center, Guangdong Provincial Key Laboratory of Major Obstetric Disease, Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology, The Third Affiliated Hospital, Guangzhou Medical University, Guangzhou, 510623, China. Electronic address: [email protected].
  • 8. Department of Hepatobiliary Surgery, Guangdong Provincial Key Laboratory of Major Obstetric Disease, Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology, The Third Affiliated Hospital, Guangzhou Medical University, Guangzhou, 510150, China. Electronic address: [email protected].
  • 9. Biomedicine Research Center, Guangdong Provincial Key Laboratory of Major Obstetric Disease, Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology, The Third Affiliated Hospital, Guangzhou Medical University, Guangzhou, 510623, China. Electronic address: [email protected].
PMID: 42202975 DOI: 10.1016/j.canlet.2026.218616
Abstract

Hepatocellular carcinoma (HCC) exhibits diminished capacity for oxidative utilization of long-chain Fatty Acids (LCFAs). However, the strategic and mechanistic basis by which HCC cells enact metabolic reprogramming to adapt to impaired LCFAs oxidation and sustain viability remains incompletely defined. Here we report that solute carrier family 27 member 5 (SLC27A5), the specific transporter for LCFAs, is broadly downregulated in HCC cells, resulting in reduced LCFAs uptake. In HCC cells with impaired LCFAs oxidation, diminished LCFAs import caused by SLC27A5 loss does not lead to energy deficiency, but instead prevents lipotoxicity derived from unutilized LCFAs, thereby supporting HCC cell growth. Impaired LCFAs oxidation suppresses Peroxisome Proliferator-activated Receptor alpha (PPAR-α) signaling, which in turn represses SLC27A5 transcription, accounting for the widespread downregulation of SLC27A5 in HCC. Owing to reduced LCFAs uptake, HCC cells with low SLC27A5 rely on the glutamine reductive pathway for fatty acid biosynthesis to maintain total fatty acid levels, rendering these cells highly sensitive to Glutaminase inhibition. In conclusion, we demonstrate that SLC27A5 downregulation represents a response to defective LCFAs oxidation in HCC, and reduced LCFAs uptake consequent to low SLC27A5 expression constitutes a survival adaptation that enables HCC to tolerate impaired LCFAs oxidation. Glutaminase inhibitors may serve as a precision therapeutic strategy for HCC characterized by low SLC27A5 expression.

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