Targeting PDK4 attenuates neointimal hyperplasia and regulates VSMC phenotypic switching, apoptosis, and autophagy

Feb 13, 2026Biochemical pharmacology

Reducing PDK4 lessens artery wall thickening by controlling muscle cell behavior, death, and self-cleaning

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Abstract

Inhibition of PDK4 using PDK4-IN-1 significantly reduced neointimal hyperplasia in a mouse carotid artery injury model.

PDK4 is linked to the regulation of vascular smooth muscle cell (VSMC) functions such as proliferation and migration.
Pharmacological inhibition of PDK4 suppressed the proliferation and migration of VSMCs stimulated by PDGF-BB.
PDK4 inhibition led to upregulation of contractile markers and a decrease in matrix metalloproteinases (MMP2 and MMP9).
Increased oxidative stress markers and apoptosis were observed following PDK4 inhibition.
Enhanced autophagic flux was detected, indicated by elevated levels of LC3 and Beclin-1.
The findings suggest that PDK4 may play a critical role in VSMC behavior and neointimal formation.

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Neointimal hyperplasia, a predominant cause of restenosis and atherosclerosis, is regulated by the phenotypic modulation, migration and proliferation, of vascular smooth muscle cells (VSMCs). Pyruvate dehydrogenase kinase 4 (PDK4) has been identified as a key metabolic regulator linked to cancer cell proliferation. However, the specific mechanistic role of PDK4 in VSMC function and neointimal formation remains ambiguous. A combination of in-silico network pharmacology, in vitro primary murine VSMC assays, and in vivo mouse carotid artery wire injury models was used to study the role of PDK4. In-silico analysis revealed that the PDK4 inhibitor (PDK4-IN-1) modulates diverse biological processes, molecular functions, and KEGG pathways central to VSMC proliferation, apoptosis, differentiation, and vascular remodelling. Pharmacological inhibition of PDK4 using PDK4-IN-1 substantially suppressed proliferation and migration of PDGF-BB-stimulated VSMCs. PDK4 inhibition upregulated contractile markers (SM22α, α-SMA, SM-MHC), reduced transcript levels of MMP2 and MMP9, and attenuated ERK and mTOR activation. It also increased cytosolic and mitochondrial ROS, lowered glutathione levels, and enhanced oxidative stress markers. Apoptosis was significantly upregulated, indicated by elevated Annexin V/PI, TUNEL positivity, BAX/BAK transcription and upregulation of caspase-3. Concurrently, autophagic flux was enhanced, with increased LC3, Beclin-1, and expression of ATG7, and LAMP1. In vivo, perivascular delivery of PDK4-IN-1 in the mouse carotid artery injury model significantly ameliorated neointimal hyperplasia. Inhibition of PDK4 perturbs pathological VSMC phenotypic switching, suppresses proliferation, promotes apoptosis and autophagy, and mitigates neointimal formation, highlighting PDK4 as a promising therapeutic target for vascular proliferative diseases.

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Targeting PDK4 attenuates neointimal hyperplasia and regulates VSMC phenotypic switching, apoptosis, and autophagy

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