Multi-omics and experimental validation reveal the proliferative mechanism of ACSL4 in pulmonary hypertension and identify potential FDA-approved drugs via in silico screening.
Chen W, Dong Y, et al. • Vascular pharmacology • 2026
ACSL4 fuels pulmonary artery smooth muscle cell growth in pulmonary hypertension through reshaping fatty acid metabolism and targeting the VGLL4/YAP signaling axis, and three FDA-approved drugs were identified as potential ACSL4 inhibitors via in silico screening.
Key Findings
Results
ACSL4 was identified as a central regulator of fatty acid metabolism in pulmonary hypertension through analysis of transcriptome data and protein interaction networks.
PH-related transcriptome data from GSE113439 was analyzed alongside protein interaction networks to pinpoint central fatty acid metabolism genes.
ACSL4 stood out as a central player in fatty acid metabolism in PH.
Functional analysis showed ACSL4 and its related networks are involved in lipid metabolism, PPAR signaling, and ferroptosis.
Results
High ACSL4 expression in pulmonary hypertension was linked to changes in the immune environment and early disease stages.
Immune cell infiltration analysis was used to explore the role of ACSL4 in the PH immune environment.
Single-cell RNA sequencing data (GSE210248) was used to characterize ACSL4's role across disease stages.
High ACSL4 expression was associated with early disease stages specifically.
Results
Virtual screening and molecular dynamics simulations identified three FDA-approved drugs that bind tightly and steadily to ACSL4.
Molecular docking and dynamics simulations were used to screen FDA-approved drugs for potential ACSL4 inhibitors.
Three FDA-approved drugs were identified as binding tightly and steadily to ACSL4.
The specific three drugs are not named in the abstract but were identified through in silico screening methods.
Results
ACSL4 levels were elevated in lung tissue and pulmonary artery smooth muscle cells (PASMCs) exposed to low oxygen, accompanied by shifts in fatty acid profiles and increased PASMC proliferation.
Studies were conducted in a rat model of PH induced by chronic low oxygen.
Primary PASMCs were also used to validate findings in vitro.
Elevated ACSL4 levels were accompanied by shifts in fatty acid profiles and increased PASMC growth under hypoxic conditions.
Results
Blocking or silencing ACSL4 reduced PASMC overgrowth by restoring normal VGLL4/YAP levels and reversing suppression of the Hippo pathway.
ACSL4 was inhibited using the inhibitor PRGL493 or siRNA knockdown.
Blocking ACSL4 eased PASMC overgrowth by helping restore normal VGLL4/YAP levels.
Inhibition of ACSL4 reversed the suppression of the Hippo pathway.
The role of ACSL4 via the VGLL4/YAP axis is described as a novel finding, distinct from previously reported roles of ACSL4 in pulmonary hypertension.
Conclusions
ACSL4 promotes PASMC proliferation in pulmonary hypertension through a mechanism involving reshaping of fatty acid metabolism and targeting the VGLL4/YAP signaling axis.
The VGLL4/YAP signaling axis was identified as a downstream target of ACSL4-mediated fatty acid metabolic reprogramming.
Although the role of ACSL4 in pulmonary hypertension has been previously reported, its function via the VGLL4/YAP axis is described as a novel finding.
Findings were validated using both in vitro (primary PASMCs) and in vivo (rat hypoxia model) experimental systems.
Multi-omics data including transcriptomics and single-cell RNA sequencing were integrated with experimental validation.
What This Means
Pulmonary hypertension (PH) is a serious disease in which the blood vessels in the lungs become narrowed due to excessive growth of smooth muscle cells in the artery walls. This study investigated a protein called ACSL4, which plays a role in how cells process fatty acids, to understand whether it contributes to this abnormal cell growth. Using large-scale gene and protein data from patient samples, combined with computer modeling and laboratory experiments in rats and cell cultures, the researchers found that ACSL4 is abnormally elevated in PH and drives the excessive growth of pulmonary artery smooth muscle cells by altering fat metabolism and disrupting a cellular signaling system called the Hippo pathway—specifically by affecting proteins called VGLL4 and YAP. When ACSL4 was blocked (either with a chemical inhibitor called PRGL493 or by silencing the gene with siRNA), the abnormal cell growth was reduced and the Hippo pathway activity was partially restored.
The researchers also used computational drug screening to identify three already-approved drugs that appear to physically bind to and potentially inhibit ACSL4, suggesting these existing medications could possibly be repurposed for treating PH without the lengthy approval process required for entirely new drugs. The connection between ACSL4 and the VGLL4/YAP signaling axis is described as a new finding that adds to what was previously known about ACSL4 in this disease.
This research suggests that ACSL4 could be a meaningful therapeutic target in pulmonary hypertension, and that disrupting its ability to alter fatty acid metabolism may help slow the dangerous remodeling of lung blood vessels. The identification of FDA-approved drugs as candidate ACSL4 inhibitors provides a potentially faster path toward new treatment options, though further clinical studies would be needed to confirm safety and effectiveness in patients.
Chen W, Dong Y, Shi Q, Meng H, Sun J, Han C, et al.. (2026). Multi-omics and experimental validation reveal the proliferative mechanism of ACSL4 in pulmonary hypertension and identify potential FDA-approved drugs via in silico screening.. Vascular pharmacology. https://doi.org/10.1016/j.vph.2026.107694