# Hyperglycemia-induced P300/CBP acetyltransferase drives ZEB2-mediated proinflammatory macrophages and delays wound healing

## TL;DR

High blood sugar increases ZEB2 in wound macrophages, causing inflammation and slower healing, but blocking ZEB2 or P300 can reverse this.

## Contribution

Identifies P300-mediated ZEB2 upregulation as a novel mechanism linking hyperglycemia to impaired wound healing.

## Key findings

- Hyperglycemia increases ZEB2 in wound macrophages via P300/CBP histone acetylation.
- ZEB2 promotes proinflammatory macrophage polarization and delays wound healing.
- P300 inhibition with C646 reduces ZEB2 and accelerates wound healing in diabetic mice.

## Abstract

Chronic hyperglycemia changes the expression of various transcription factors and mRNA transcripts that impair cellular functionality and delay wound healing. Zinc finger E-box–binding homeobox 2 (ZEB2), a key transcription factor, maintains tissue-specific macrophage identities; however, its role in regulating macrophage polarization during wound healing under hyperglycemic conditions remains unclear. Here, we found that persistent hyperglycemia increases ZEB2 expression in wound macrophages via histone acetylation, contributing to chronic inflammation and delayed wound healing. Exposure to high glucose levels activated P300/CBP, a transcriptional coactivator involved in histone acetylation, which enhanced ZEB2 expression in wound macrophages. The forced expression of ZEB2 shifted macrophage polarity toward a proinflammatory state by upregulating myeloid lineage–directed transcription factors. Conversely, silencing Zeb2 at the wound site reduced hyperglycemia-induced macrophage inflammation. Topical application of C646, an inhibitor of P300, at the wound edges of streptozotocin-induced high-fat diet–fed diabetic mice significantly decreased ZEB2 expression, reduced inflammation, and accelerated wound healing. Therefore, targeted inhibition of P300 represents a promising therapeutic strategy for improving diabetic wound healing by modulating ZEB2-driven inflammation in wound macrophages.

Hyperglycemia-induced ZEB2 expression via P300 drives inflammation, and delays wound healing. Silencing ZEB2 or using the P300 inhibitor C646 reduces inflammation and promotes wound healing.