# Hypoxic Reprogramming of ACOX1-Driven HSP90AB1 Crotonylation Stabilizes Thioredoxin to Orchestrate Redox Homeostasis in Oral Squamous Cell Carcinoma

## TL;DR

This study shows how hypoxia helps oral cancer cells survive by altering a protein modification that stabilizes another protein to control harmful oxygen levels.

## Contribution

The study identifies a novel hypoxia-driven crotonylation mechanism involving HSP90AB1 and TXN in oral cancer.

## Key findings

- Hypoxia increases ACOX1, leading to HSP90AB1 crotonylation and TXN stabilization.
- Crotonylated HSP90AB1 enhances redox balance and promotes tumor growth and cisplatin resistance.
- Blocking the ACOX1–HSP90AB1–TXN axis synergizes with cisplatin to reduce tumor growth in mice.

## Abstract

Hypoxia promotes oral squamous cell carcinoma (OSCC) progression by disrupting redox equilibrium; however, how tumor cells precisely calibrate prosurvival reactive oxygen species levels remains unclear. This study identifies a hypoxia-inducible signaling axis centered on the posttranslational crotonylation of the molecular chaperone heat shock protein 90 alpha family class B member 1 (HSP90AB1), which stabilizes thioredoxin (TXN) to constrain oxidative stress. Hypoxia triggered the hypoxia-inducible factor-1α (HIF-1α)-dependent transcriptional up-regulation of acyl-CoA oxidase 1 (ACOX1), increasing the level of crotonyl-CoA to drive the site-specific crotonylation of HSP90AB1 at lysine 265 (K265cr). Molecular dynamics simulations revealed that K265 crotonylation induced the conformational compaction of HSP90AB1, strengthening its interaction with TXN and enhancing its stability. This chaperone–client axis effectively buffers reactive oxygen species to protumorigenic thresholds, promoting proliferation and conferring cisplatin resistance. Clinically, HIF-1α/ACOX1/HSP90AB1 K265cr/TXN pathway activation is correlated with advanced disease and reduced survival in OSCC patients. Crucially, the HSP90AB1 K265R mutation or pharmacological inhibition of ACOX1 (10,12-tricosadiynoic acid) or TXN (1-methyl-propyl 2-imidazolyl disulfide, PX-12) synergizes with cisplatin to suppress tumor growth in vivo by disrupting redox adaptation. These findings reveal that crotonylation is a hypoxia-sensitive rheostat for TXN-mediated redox control, suggesting that the ACOX1–HSP90AB1–TXN axis is a therapeutic vulnerability in therapy-resistant OSCC.