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  3. Pregnenolone promotes immune evasion through blocking endogenous retrovirus expression

Pregnenolone promotes immune evasion through blocking endogenous retrovirus expression

  • Cell Metab. 2026 Jan 23:S1550-4131(25)00584-4. doi: 10.1016/j.cmet.2025.12.020.
Changsheng Huang 1,  Huanyu Tao 2,  Yuhan Zhou 3,  Qi Wu 4,  Mao Li 4,  Anyi Liu 4,  Tong Zhu 4,  Chengxin Yu 4,  Pengcheng Li 4,  ShengYou Huang 2,  Huan Guo 3,  Junbo Hu 5,  Guihua Wang 6
Affiliations

Affiliations

  • 1 GI Cancer Research Institute, Tongji Hospital, State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Wuhan 430030, P.R. China; Hubei Provincial Key Laboratory of Cancer Neuroscience, Wuhan 430030, P.R. China.
  • 2 School of Physics, Huazhong University of Science and Technology, Wuhan 430074, Hubei, China.
  • 3 Department of Occupational and Environmental Health, State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China.
  • 4 GI Cancer Research Institute, Tongji Hospital, State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Wuhan 430030, P.R. China.
  • 5 GI Cancer Research Institute, Tongji Hospital, State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Wuhan 430030, P.R. China; Hubei Provincial Key Laboratory of Cancer Neuroscience, Wuhan 430030, P.R. China. Electronic address: [email protected].
  • 6 GI Cancer Research Institute, Tongji Hospital, State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Wuhan 430030, P.R. China; Hubei Provincial Key Laboratory of Cancer Neuroscience, Wuhan 430030, P.R. China; Brain-Computer Interface Research Institute, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China. Electronic address: [email protected].
PMID: 41579859 DOI: 10.1016/j.cmet.2025.12.020
Abstract

Research into steroid Hormones shaping tumor biology has gained increasing attention. Using multiple mouse tumor models, we show that pregnenolone promoted tumor progression and reduced sensitivity to immunotherapy. Pregnenolone levels were markedly elevated in maternal mice experiencing mating deficiency. Mechanistically, pregnenolone directly binds Kap1 and inhibits Trim39-mediated ubiquitination at K750, leading to Kap1 stabilization and repression of endogenous retrovirus (ERV) expression and type-I interferon production. Furthermore, pharmacological antagonism of pregnenolone effectively suppressed tumor growth and enhanced immunotherapy efficacy. These findings reveal a previously unrecognized link between mating-associated steroid metabolism and tumor immune regulation and identify pregnenolone signaling as a potential therapeutic target in Cancer.

Keywords

Kap1; endogenous retrovirus; immune evasion; pregnenolone.

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