2. Academic Validation
  3. Blocking Lysine Crotonylation and Aerobic Glycolysis as Targeting Strategy Against mpox Virus Replication

Blocking Lysine Crotonylation and Aerobic Glycolysis as Targeting Strategy Against mpox Virus Replication

  • Adv Sci (Weinh). 2025 Oct 27:e09148. doi: 10.1002/advs.202509148.
Pengjun Wei 1,  Zongzheng Zhao 2,  Ruoqi Xu 1,  Qin Yan 1,  Liangzi Jiang 1,  Fuxiao Geng 1,  Yang Gu 1,  Tianjiao Wang 1,  Jing Zhou 1,  Xiao Li 2,  Qin Yan 1 3,  Chun Lu 1 3 4,  Wan Li 1 3 4
Affiliations

Affiliations

  • 1 Department of Microbiology, Nanjing Medical University, Nanjing, 211166, P. R. China.
  • 2 Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, 130122, P. R. China.
  • 3 Key Laboratory for Pathogen Infection and Control of Jiangsu Province, Nanjing Medical University, Nanjing, 211166, P. R. China.
  • 4 Department of Infectious Diseases, Changzhou Third People's Hospital, Changzhou Medical Center, Nanjing Medical University, Nanjing, 211166, P. R. China.
PMID: 41144710 DOI: 10.1002/advs.202509148
Abstract

The global outbreak of mpox caused by the mpox virus (MPXV) in 2022 and 2024 underscores the urgent need to elucidate mechanisms governing viral replication during pathogenesis. Metabolic reprogramming is a conserved hallmark of viral infections, however, the precise mechanisms by which MPXV manipulates host cell metabolism remain unknown. Here, it is demonstrated that MPXV hijacks aerobic glycolysis via lysine crotonylation of its I3 protein, which is essential for MPXV replication. Mechanistically, MYST Histone Acetyltransferase 1 (MYST1), an acetyltransferase upregulated by MPXV, binds to and catalyzes the crotonylation of I3. The crotonylated I3 interacts with WD-repeat protein 26 (WDR26) to prevent its ubiquitination-dependent degradation, leading to enhanced aerobic glycolysis and promoting MPXV replication. Either pharmacological inhibition of MYST1 using MC4033 or blocking aerobic glycolysis with the glycolytic inhibitors 2-Deoxy-D-glucose (2-DG) or dichloroacetic acid (DCA) effectively suppresses MPXV replication. These findings uncover a novel crotonylation-dependent mechanism through which MPXV reprograms host metabolism to facilitate viral propagation, and identify lysine crotonylation and aerobic glycolysis as potential therapeutic targets against mpox.

Keywords

I3; MYST1; aerobic glycolysis; crotonylation; mpox virus.

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