2. Academic Validation
  3. AKR1C3 promotes aerobic glycolysis in hepatic stellate cells via the AKT/mTOR pathway to induce liver fibrosis

AKR1C3 promotes aerobic glycolysis in hepatic stellate cells via the AKT/mTOR pathway to induce liver fibrosis

  • Cell Signal. 2026 May:141:112369. doi: 10.1016/j.cellsig.2026.112369.
Tao Ran 1,  Qing-Xiu Zhang 1,  Hua-Yue Wu 1,  Shu Feng 1,  Lu Han 1,  Yuan Qin 2,  Guo-Yuan Lin 3,  Ya Zhang 4,  Shi-Liang Li 5,  Ji-Yu Chen 6,  Yu-Mei Zhou 1,  Shi-Qian Cai 7,  Xue-Ke Zhao 8
Affiliations

Affiliations

  • 1 Department of Infectious Disease, The Affiliated Hospital of Guizhou Medical University, Guiyang 550000, China.
  • 2 Department of Gastroenterology, Yanhe Tujia autonomous County People's Hospital, Yanhe 565300, China.
  • 3 Department of Cardiology, Guiqian International General Hospital, Guiyang, Guiyang 550000, China.
  • 4 Department of Infectious Disease, The Affiliated Hospital of Guizhou Medical University, Guiyang 550000, China; Department of Gastroenterology, The Affiliated Jinyang Hospital of Guizhou Medical University, Guiyang 550000, China.
  • 5 Department of Vascular Surgery, The Affiliated Hospital of Guizhou Medical University, Guiyang 550000, China.
  • 6 Clinical Trials Center, The Affiliated Hospital of Guizhou Medical University, Guiyang 550000, China.
  • 7 Department of Gastroenterology, The First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang 550000, China.
  • 8 Department of Infectious Disease, The Affiliated Hospital of Guizhou Medical University, Guiyang 550000, China. Electronic address: [email protected].
PMID: 41554490 DOI: 10.1016/j.cellsig.2026.112369
Abstract

Liver fibrosis (LF) represents a common wound-healing response to various forms of liver injury. Activation of hepatic stellate cells (HSCs) is a central event in this process. Aerobic glycolysis plays a critical role in the sustained activation of HSCs. Human aldo-keto reductase family 1 member C3 (AKR1C3), a multifunctional enzyme, is upregulated in many diseases and has been identified as a drug target in Cancer treatment. However, the underlying mechanism through which AKR1C3 is involved in LF remains unclear. This study indicated the elevated expression of AKR1C3 in the fibrotic tissues of both humans and rats. AKR1C3 overexpression stimulated the proliferation, migration, and activation of HSCs in vitro. These effects were reversed by inhibiting AKR1C3. Based on RNA-seq analysis, we investigated the underlying mechanism of AKR1C3 and found that glycolysis and the Akt/mTOR pathway may contribute to the effect of AKR1C3 on LF. Mechanistically, AKR1C3 may act as a molecular scaffold to mediate the binding of mTORC2 to Akt, thereby promoting the phosphorylation of Akt at Ser473 and activating the signaling pathway. In addition, AKR1C3 overexpression promoted aerobic glycolysis in HSCs by activating the Akt/mTOR pathway, but these effects were partly reversed by glycolysis inhibitors (2-DG) and Akt inhibitors (MK-2206). Our findings revealed the mechanism by which AKR1C3 promotes LF, suggesting that AKR1C3 may serve as a potential therapeutic target for LF, warranting further studies.

Keywords

AKR1C3; AKT/mTOR signaling pathway; Aerobic glycolysis; Hepatic stellate cells; Liver fibrosis.

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