TRIM24 Impediment suppresses VSMC modulation and attenuates neointimal hyperplasia via redox and autophagy pathways.

Authors

Monika Singh, Ankan Sarkar, Zahid Bashir Zargar, Yashdeep Mukheja, Sandip V Pawar, Kanwaljit Chopra, Manish Jain

Published in

Molecular biology reports. Volume 53. Issue 1. Jul 29, 2026. Epub Jul 29, 2026.

Abstract

Excessive vascular smooth muscle cell (VSMC) proliferation/survival is a critical event underlying restenosis and vascular remodeling. Tripartite motif-containing 24 (TRIM24) is an oncogenic TRIM family protein with E3 ubiquitin ligase and transcriptional co-regulator functions. This study aimed to elucidate the critical role of TRIM24 in modulating VSMC functions and neointimal hyperplasia.
Our in-silico network pharmacology analysis revealed that the TRIM24 inhibitor, IACS-9571, engages multiple hub genes and key pathways involved in VSMC proliferation, apoptosis, autophagy, migration, and extracellular matrix remodeling. Using Western blot and immunofluorescence analysis, we found that platelet-derived growth factor-BB (PDGF-BB) stimulation of murine primary aortic VSMCs, significantly upregulated TRIM24 expression. SiRNA-mediated knockdown of TRIM24 attenuated PDGF-BB-induced VSMC proliferation. Pharmacological inhibition of TRIM24 using IACS-9571 markedly suppressed PDGF-BB-induced VSMC proliferation, migration, and phenotypic switching. Furthermore, TRIM24 blockade enhanced autophagy in VSMCs, as evidenced by elevated LC3 and Beclin-1 protein levels, accumulation of LC3 puncta and transcriptional upregulation of autophagy-related genes, namely ATG7 and ATG4B. Also, TRIM24 inhibition reduced AKT and mTOR activation compared to PDGF-BB-stimulated VSMCs. Concurrently, TRIM24 inhibition elevated mitochondrial ROS levels, upregulated BAX expression, a pro-apoptotic gene, and significantly enhanced apoptosis, as confirmed by TUNEL and Annexin V/PI assays. In vivo, Immunofluorescence analysis demonstrated elevated TRIM24 expression within the neointimal regions. Perivascular application of the TRIM24 inhibitor prevented wire injury-induced neointimal hyperplasia.
These findings identify TRIM24 as a key regulator of VSMC proliferation, migration, and phenotypic switching. Targeting TRIM24 promotes autophagy and induces apoptosis, offering a promising strategy to limit neointimal hyperplasia and pathological vascular remodeling.

PMID:
42525139
Bibliographic data and abstract were imported from PubMed on 29 Jul 2026.

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