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.

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.

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