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REVIEW article

Front. Med.

Sec. Hepatobiliary Diseases

Volume 12 - 2025 | doi: 10.3389/fmed.2025.1617401

Mechanisms and Potential Therapeutic Targets of SphK1 and SphK2 in Hepatocellular Carcinoma (HCC)

Provisionally accepted
Xiaoying  XuXiaoying Xu1,2,3hengfei  lihengfei li2*Ruisi  LiRuisi Li1yue  Xuyue Xu1Yiheng  XuYiheng Xu1Haitang  HuangHaitang Huang2xiaojuan  lvxiaojuan lv2liao  chuliao chu2junqiu  yejunqiu ye2bo  liubo liu2
  • 1Hubei University of Chinese Medicine, Wuhan, China
  • 2Hubei Provincial Hospital of Traditional Chinese Medicine, Wuhan, Hubei Province, China
  • 3Department of Hepatology, Hubei Provincial Hospital of Traditional Chinese Medicine, Wuhan, Hebei Province, China

The final, formatted version of the article will be published soon.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths globally. Sphingosine-1-phosphate (S1P) is catalyzed by sphingosine kinases SphK1 and SphK2 and plays a key role in HCC progression: SphK1 can drive tumor proliferation, migration, and angiogenesis. It activates the PI3K/AKT/mTOR and MAPK/ERK signaling pathways and mediates chemoresistance and immune suppression; SphK2 enhances histone acetylation and upregulates pro-oncogene expression through nuclear S1P. It also maintains telomere activity via mitochondrial S1P, which promotes tumor survival and facilitates resistance to regorafenib. In targeted therapy, SphK1 inhibitors (e.g., PF-543) and SphK2 inhibitors (e.g., ABC294640) have shown significant anti-tumor effects in preclinical models. Future research should focus on elucidating the regulatory networks of SphK1/SphK2 in different HCC subtypes, developing highly selective inhibitors, and advancing clinical trials based on metabolic-immune interaction regulation. This paper systematically summarizes the mechanisms of action and therapeutic progress of SphK1/SphK2 in HCC. It provides an important theoretical basis for the clinical translation of precision therapy strategies in HCC.

Keywords: HCC, S1P, SPHK1, SPHK2, Mechanism

Received: 24 Apr 2025; Accepted: 16 Oct 2025.

Copyright: © 2025 Xu, li, Li, Xu, Xu, Huang, lv, chu, ye and liu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: hengfei li, 26877767@qq.com

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