2. Academic Validation
  3. Procyanidin C1 ameliorates aging-related skin fibrosis through targeting EGFR to inhibit TGFβ/SMAD pathway

Procyanidin C1 ameliorates aging-related skin fibrosis through targeting EGFR to inhibit TGFβ/SMAD pathway

  • Phytomedicine. 2025 Jul:142:156787. doi: 10.1016/j.phymed.2025.156787.
Jun-Han Wang 1,  Min Li 1,  Peng-Fei Xie 1,  Jia-Yao Si 1,  Zhen-Jie Feng 1,  Chuan-Feng Tang 2,  Jian-Mei Li 3
Affiliations

Affiliations

  • 1 School of Food Science and Pharmaceutical Engineering, Nanjing Normal University, Nanjing 210023, China.
  • 2 State Key Laboratory of Technologies for Chinese Medicine Pharmaceutical Process Control and Intelligent Manufacture, Nanjing University of Chinese Medicine, Nanjing 210023, China. Electronic address: tangchuanfeng@njucm.edu.cn.
  • 3 School of Food Science and Pharmaceutical Engineering, Nanjing Normal University, Nanjing 210023, China. Electronic address: lijianmei@njnu.edu.cn.
PMID: 40315640 DOI: 10.1016/j.phymed.2025.156787
Abstract

Background: Aging-related skin fibrosis (SF) is a complex condition with limited treatment options. Procyanidin C1 (PCC1), a natural polyphenolic compound with demonstrated senolytic activity, has emerged as a potential therapeutic agent for fibrotic disorders through its selective elimination of senescent cells. However, its therapeutic efficacy and mechanisms in aging-related SF remain unclear.

Purpose: This study aimed to investigate the mechanisms of PCC1 in aging-related SF.

Results: In D-galactose-induced L929 cells, PCC1 treatment significantly attenuated the expression of both senescence-associated markers (IL-1β, P16, P21 and LMNB1) and fibrosis-related markers (α-SMA, LOXL2 and COL1). Network pharmacology and experimental validation (molecular docking, DARTS, CETSA, MST) identified EGFR as a primary target, with PCC1 directly binding to and inhibiting EGFR phosphorylation. Furthermore, PCC1 treatment effectively down-regulated TGFβ1 expression and suppressed SMAD2/3 phosphorylation in D-galactose-induced L929 cells. Notably, PCC1 blocked NSC228155-induced EGFR phosphorylation and inhibited ERK/MAPK, Akt/mTOR and TGFβ/SMAD pathway activation. In bleomycin-induced SF mice, PCC1 significantly attenuated epidermal hyperplasia, improved Collagen structure, restored the Collagen I/III ratio, and reduced EGFR phosphorylation along with TGFβ1 expression and SMAD2/3 phosphorylation.

Conclusion: This study elucidates that PCC1 exerts its anti-fibrotic effects through dual mechanisms: resistance to cellular senescence and modulation of fibroblast heterogeneity. By directly binding to EGFR and inhibiting its phosphorylation, PCC1 subsequently suppresses multiple downstream signaling cascades, ultimately ameliorating TGFβ/SMAD-mediated SF. These findings establish PCC1 as a promising therapeutic candidate for aging-related skin fibrosis, offering a novel approach through targeted EGFR inhibition and comprehensive pathway modulation.

Keywords

EGFR; Procyanidin C1; Senescent fibroblasts; Skin fibrosis; TGFβ/SMAD pathway.

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