SEPHS2 loss reprograms cancer metabolism from oxidative phosphorylation to gluconeogenesis via PCK1 stabilization
levels, thereby activating the deacetylase SIRT2 as a cofactor and promoting deacetylation-dependent stabilization of the gluconeogenic enzyme PCK1. Under selenium-limited conditions, SEPHS2 is reduced. SEPHS2 loss promotes tumor spread to the lung and sensitizes tumors to the PPP inhibitor 6-aminonicotinamide. These findings define a selenoprotein biosynthesis-independent role of SEPHS2 in regulating OXPHOS and unveil the PPP as a therapeutic vulnerability in tumors adapting to a selenium-limited microenvironment.
Authors
- Weibo Zhang
- Siyuan Xia (ORCID: https://orcid.org/0000-0001-6756-3519)
- 麦风仪
- Weijian Ding (ORCID: https://orcid.org/0000-0002-3721-9896)
- Xiancai Du (ORCID: https://orcid.org/0000-0003-2527-6671)
- Wenzhou Wang (ORCID: https://orcid.org/0009-0003-2994-9308)
- Y Zhang
- Jingnan Huang (ORCID: https://orcid.org/0000-0001-6471-8693)
- Wenyou He
- Yu Zhang (ORCID: https://orcid.org/0000-0002-0694-6409)
- Linyue Li
- Yuchun Niu
- Yirui Ye
- Jiali Xu
- Keyu Zhao
- Xinyu Chen
- Bi Wei
- Chenguang Li
- Qinghua Zhang
- Baotong Zhang
- Zining Zhao
- Lingyun Dai
Institutions
- Southern University of Science and Technology (CN)
- Shenzhen Sixth People's Hospital (CN)
- First People's Hospital of Foshan (CN)
- Anshan Hospital (CN)
Publication Details
- Journal
- Cell Reports
- Published
- 2026-04-25
- DOI
- https://doi.org/10.1016/j.celrep.2026.117297
- Primary Topic
- Cancer, Hypoxia, and Metabolism
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- National Natural Science Foundation of China
- Guangdong Science and Technology Department
- Science, Technology and Innovation Commission of Shenzhen Municipality