Post-translational switch of DHCR24 acetylation sustains sterol synthesis and promotes HCC via the 7-ketocholesterol/p62 axis
Dysregulated cholesterol synthesis fuels cancer progression, but its precise role in hepatocellular carcinoma (HCC) remains unclear. Here, we identify elevated acetylation of 24-dehydrocholesterol reductase (DHCR24) at Lys254 as a hallmark of HCC. Both total DHCR24 and its K254 acetylation independently predict poor patient survival. Acetylation stabilizes DHCR24, sustaining hepatic cholesterol synthesis and promoting tumorigenesis. Mechanistically, DHCR24 acetylation enhances 7-ketocholesterol accumulation, which upregulates p62 and drives HCC growth in vitro and in vivo. Pharmacologic inhibition of DHCR24 expression and acetylation with the US Food and Drug Administration (FDA)-approved drug irbesartan suppresses cell proliferation and reduces tumor burden in xenograft and carcinogen-induced mouse models. Reduced p62 expression parallels the antitumor effects. These findings define DHCR24 acetylation as a metabolic switch linking sterol synthesis to oncogenesis and highlight the DHCR24-7-ketocholesterol-p62 axis as a therapeutic target for HCC.
Authors
- Liuyang Zhao (ORCID: https://orcid.org/0000-0001-7559-5131)
- Hongxue Meng (ORCID: https://orcid.org/0000-0002-1831-2737)
- Xinxin Yang (ORCID: https://orcid.org/0000-0002-2024-4307)
- Ran Ju (ORCID: https://orcid.org/0000-0002-4756-4757)
- Jianwen Xu (ORCID: https://orcid.org/0000-0002-8095-591X)
- Dabin Liu (ORCID: https://orcid.org/0000-0002-3811-8317)
- Shuyuan Chang
- Lei Yu (ORCID: https://orcid.org/0000-0003-0010-9228)
- Yunjing Hou
- Qiang Fu (ORCID: https://orcid.org/0000-0002-6932-7103)
- Yihong Dong
- Chenxu Guo (ORCID: https://orcid.org/0000-0002-9651-4203)
- Shuo Li (ORCID: https://orcid.org/0000-0002-5184-3230)
- Yunfei Zhou
- Yumeng Wang (ORCID: https://orcid.org/0000-0001-9050-930X)
- Jun Yan
- Yang Xun (ORCID: https://orcid.org/0000-0001-7950-4778)
- Feng Geng (ORCID: https://orcid.org/0000-0002-2985-0629)
- Qingxin Zhang (ORCID: https://orcid.org/0000-0002-1748-2005)
- Yidi Wu (ORCID: https://orcid.org/0000-0002-9614-1312)
- Yin Fu
- Xiaoyang Hu
- Tomii Ayaka
Institutions
- Harbin Medical University (CN)
- Heilongjiang University of Chinese Medicine (CN)
- Third Affiliated Hospital of Harbin Medical University (CN)
- Fourth Affiliated Hospital of Harbin Medical University (CN)
- Second Affiliated Hospital of Harbin Medical University (CN)
- Chongqing Medical University (CN)
Publication Details
- Journal
- Cell Reports
- Published
- 2025-12-01
- DOI
- https://doi.org/10.1016/j.celrep.2025.116640
- Citations
- 1
- Primary Topic
- Cancer, Lipids, and Metabolism
- Type
- article
- Field-Weighted Citation Impact
- 0.94