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

## TL;DR

This paper shows how the mpox virus uses a chemical modification called crotonylation to boost cell metabolism and replicate, and how blocking this process could help treat mpox.

## Contribution

The study identifies a novel crotonylation-dependent mechanism by which MPXV reprograms host metabolism to enhance replication.

## Key findings

- MPXV uses the I3 protein's crotonylation to promote aerobic glycolysis and replication.
- MYST1 acetyltransferase catalyzes I3 crotonylation, preventing WDR26 degradation.
- Inhibiting MYST1 or glycolysis with drugs like 2-DG or DCA suppresses MPXV replication.

## 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.

Wei et al. report that MPXV infection induces aerobic glycolysis, a process mediated by the viral protein I3 through lysine crotonylation at its K102 residue. The acetyltransferase MYST1 catalyzes the crotonylation of I3 to inhibit the ubiquitin‐mediated degradation of WDR26. Consequently, this process promotes both aerobic glycolysis and viral replication. Targeting either MYST1 or aerobic glycolysis significantly impairs MPXV replication.