2. Academic Validation
  3. HKDC1 promotes the H3K18 lactylation of the promoter of ORMDL3 to induce the activation of hepatic stellate cells in liver cirrhosis

HKDC1 promotes the H3K18 lactylation of the promoter of ORMDL3 to induce the activation of hepatic stellate cells in liver cirrhosis

  • Biochim Biophys Acta Mol Basis Dis. 2025 Dec 18;1872(3):168140. doi: 10.1016/j.bbadis.2025.168140.
Yanan Zhang 1,  Lei Li 2,  Gaiqin Li 2,  Junyuan Zhu 3,  Zexue Qi 4,  Chunqing Zhang 5
Affiliations

Affiliations

  • 1 Department of Gastroenterology, Shandong Provincial Hospital, Shandong University, Jinan, Shandong, 250021, China; Department of Gastroenterology, Taian City Central Hospital, Qingdao University, Taian, Shandong, 271099, China.
  • 2 Department of Gastroenterology, Taian City Central Hospital, Qingdao University, Taian, Shandong, 271099, China.
  • 3 Department of Gastroenterology, Shandong Provincial Hospital, Shandong University, Jinan, Shandong, 250021, China.
  • 4 Department of Hepatology, Shandong Provincial Third Hospital, Jinan, Shandong, 250031, China.
  • 5 Department of Gastroenterology, Shandong Provincial Hospital, Shandong University, Jinan, Shandong, 250021, China. Electronic address: [email protected].
PMID: 41418678 DOI: 10.1016/j.bbadis.2025.168140
Abstract

Purpose: We aimed to investigate the role and possible mechanism of action of Hexokinase domain containing 1 (HKDC1) in liver cirrhosis.

Methods: Hepatic stellate cell (HSC) activation model was established in LX-2 cells by transforming growth factor (TGF)-βl stimulation. A mouse model of hepatic fibrosis was established using carbon tetrachloride (CCl4) stimulation. HKDC1 expression was assessed using qRT-PCR, western blotting, and immunofluorescence. Hematoxylin and eosin (H&E) and Masson staining were used to assess liver injury and fibrosis. Changes in fibrosis markers were assessed using qRT-PCR, western blotting, and immunohistochemical staining. The effect of HKDC1 on glycolysis was evaluated by measuring the levels of extracellular acidification rate (ECAR), oxygen consumption rate (OCR), lactate, and related proteins.

Results: In liver cirrhosis tissues and activated HSCs, HKDC1 expression was upregulated. CCl4-induced liver injury and fibrosis were inhibited by silencing of Hkdc1 in mice, as evidenced by the decrease of aspartate transaminase (AST), alanine transaminase (ALT), Collagen I, α-SMA, TGF-β1, and TIMP-1. Under TGF-β1 treatment, silencing of HKDC1 inhibited HSC activation and glycolysis, as evidenced by the reduce of Collagen I, α-SMA, TIMP-1, ECAR, lactate, HK2, LDHA, PKM2 and the increase of OCR. Mechanistically, silencing of HKDC1 reduced the levels of ORMDL3 and H3K18la proteins, and HKDC1 increased histone lactylation of the promoter of ORMDL3. ORMDL3 overexpression and lactate eliminated the effects of HKDC1 silencing on LX-2 cell activation.

Conclusion: HKDC1 silencing alleviates liver fibrosis and HSC activation by regulating glycolysis and decreasing histone lactylation of the promoter of ORMDL3.

Keywords

Glycolysis; HKDC1; Hepatic stellate cells; Liver fibrosis; ORMDL3.

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