# Epigenetic regulation by HDAC11-driven STAT3 activation promotes pro-inflammatory cytokine production and endothelial dysfunction upon bacterial infection in diabetes

## TL;DR

This study shows that HDAC11 promotes inflammation and vascular issues in diabetic patients during bacterial infections, suggesting it could be a new treatment target.

## Contribution

The study identifies HDAC11 as a novel epigenetic regulator linking diabetes, inflammation, and endothelial dysfunction during bacterial infections.

## Key findings

- HDAC11 expression is significantly higher in diabetic endothelial cells infected with E. coli.
- HDAC11 inhibition reduces pro-inflammatory cytokines and restores endothelial function in diabetic cells.
- HDAC11 interacts with STAT3 to sustain inflammation in diabetic endothelial cells.

## Abstract

Diabetes mellitus is associated with low-grade inflammation, resulting in susceptibility to infections and related complications. Histone deacetylase 11 (HDAC11) regulates host immune responses upon infections including fungal and gram-negative bacterial infections. Here, we hypothesise that bacterial infection may influence epigenetic regulation via HDAC11, resulting in the exacerbation of the inflammation responses.

Induced pluripotent stem cells (iPSCs) from non-diabetic (ND) and diabetic (DB) donors were differentiated into endothelial cells (ECs). The iPSCs-derived ECs (iPS-ECs) were infected with Escherichia coli (E. coli) to mimic sepsis. Bulk RNA sequencing was performed to validate the gene expression in transcriptomic level. qRT-PCR, ELISA, and western blot were conducted to assess gene expression levels. Immunocytochemistry (ICC) staining was used to visualise the protein expression, and functional tests were performed to assess the iPS-ECs’ response to infection.

This study revealed that HDAC11 expression is significantly elevated in iPS-ECs derived from DB donors when infected with E. coli. HDAC11 upregulation was associated with increased production of pro-inflammatory cytokines and vascular dysfunction. Administration of a HDAC11 inhibitor effectively suppressed pro-inflammatory cytokine expression and restored endothelial function. Mechanistic analyses demonstrated that interaction of HDAC11 with the signal transducer and activator of transcription 3 (STAT3) sustained the inflammatory response in iPS-ECs derived from DB donors.

Our findings highlight the role of HDAC11 to mediate inflammation-driven vascular impairment in diabetes, suggesting HDAC11 is a promising therapeutic target to mitigate endothelial dysfunction and inflammation, improving endothelial health in people with diabetes.

The online version contains supplementary material available at 10.1186/s12964-026-02696-4.