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Background <p>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.</p> Methods and results <p>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 <i>ATG7</i> and <i>ATG4B</i>. Also, TRIM24 inhibition reduced AKT and mTOR activation compared to PDGF-BB-stimulated VSMCs. Concurrently, TRIM24 inhibition elevated mitochondrial ROS levels, upregulated <i>BAX</i> 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.</p> Conclusion <p>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.</p>

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

  • 期刊论文

  • 发表日期：

    2026年7月29日

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

摘要

Background

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.

Methods and results

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.

Conclusion

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.