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Updated: Aug 24, 2025

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HDAC5-mediated Smad7 silencing through MEF2A is critical for fibroblast activation and hypertrophic scar formation

Ya Gao1, Yangdan Liu1, Danning Zheng1

  • 1Department of Plastic & Reconstructive Surgery, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.

International Journal of Biological Sciences
|October 20, 2022
PubMed

Insights

Histone deacetylase 5 (HDAC5) promotes hypertrophic scar formation by inhibiting Smad7. Inhibiting HDAC5 reduces scarring, offering a potential therapeutic strategy for fibrotic diseases.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Dermatology

Background:

  • Transforming growth factor-β (TGF-β) signaling is crucial in fibrosis.
  • Histone deacetylase 5 (HDAC5) is linked to TGF-β signaling and fibrosis, but its role in hypertrophic scarring is unclear.

Purpose of the Study:

  • To investigate the role and regulatory mechanism of HDAC5 in hypertrophic scar (HS) formation.
  • To explore HDAC5 as a potential therapeutic target for fibrotic diseases.

Main Methods:

  • Assessed HDAC5 expression in HS tissues and its effect on fibroblast activation.
  • Utilized knockdown and inhibitor studies to analyze the TGF-β/Smad signaling pathway.
  • Employed luciferase reporter and ChIP-qPCR assays to determine the interaction between HDAC5, MEF2A, and the Smad7 promoter.

Main Results:

  • HDAC5 was overexpressed in HS tissues and its depletion attenuated scar formation and fibroblast activation.
  • HDAC5 knockdown downregulated TGF-β1-induced Smad2/3 phosphorylation and increased Smad7 expression.
  • HDAC5 suppresses Smad7 expression by inhibiting MEF2A binding to the Smad7 promoter, and LMK235 alleviated HS formation.

Conclusions:

  • HDAC5 plays a significant role in hypertrophic scar formation.
  • Targeting HDAC5 presents a promising therapeutic strategy for managing fibrotic diseases like hypertrophic scarring.
Keywords:
HDAC5Hypertrophic scarMEF2ASmad7TGF-β

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