# Histone deacetylase 3 promotes hypoxia-induced human pulmonary arterial smooth muscle cell proliferation by modulating the CSF2-JAK2-STAT5 signaling pathway

## TL;DR

This study shows that HDAC3 promotes the growth of human pulmonary artery cells under low oxygen conditions by activating a specific signaling pathway, suggesting HDAC3 inhibition could help treat lung hypertension.

## Contribution

The study reveals a novel role of HDAC3 in hypoxia-induced pulmonary arterial smooth muscle cell proliferation via the CSF2-JAK2-STAT5 pathway.

## Key findings

- HDAC3 inhibition reduces hypoxia-induced proliferation of human pulmonary arterial smooth muscle cells.
- HDAC3 promotes proliferation by upregulating CSF2 and activating the JAK2/STAT5 pathway under hypoxia.
- Blocking CSF2 or JAK2/STAT5 reverses the pro-proliferative effects of HDAC3 overexpression.

## Abstract

The growth of human pulmonary arterial smooth muscle cells (hPASMCs) is one of the key contributors to vascular remodeling in pulmonary arterial hypertension (PAH). Although histone deacetylase 3 (HDAC3) has been implicated in acute lung injury and pulmonary fibrosis, its role in hypoxia-induced PAH remains unclear. Here, the function and associated mechanisms of HDAC3 in hypoxia-induced hPASMC proliferation were investigated. A hypoxia-induced hPASMC model was constructed to evaluate the role of HDAC3 in cell proliferation under hypoxic conditions. The effects of HDAC3 siRNA and ruxolitinib, a JAK pathway inhibitor, were assessed to explore the regulatory mechanism of HDAC3 in vascular remodeling. Hypoxia significantly upregulated both HDAC3 mRNA and protein. Inhibition of HDAC3 attenuated hypoxia-induced proliferation in hPASMCs. Moreover, HDAC3 inhibition downregulated CSF2 and suppressed proliferation by inactivating the JAK2/STAT5 axis. In contrast, HDAC3 overexpression enhanced CSF2 expression, activated JAK2/STAT5, and promoted hPASMCs’ proliferation under hypoxia. Notably, the pro-proliferative and pathway-activating effects of HDAC3 overexpression were reversed by CSF2 silencing or ruxolitinib treatment. HDAC3 plays a key role in hypoxia-induced hPASMC dysfunction. Its inhibition mitigates aberrant proliferation through a CSF2-dependent inactivation of the JAK2/STAT5 pathway under hypoxia. These results indicate the potential of using HDAC3 for treating hypoxia-induced PAH.

The online version contains supplementary material available at 10.1007/s13577-026-01348-6.