2. Academic Validation
  3. Drugs targeting TGF-β/Notch interaction attenuate hypertrophic scar formation by optic atrophy 1-mediated mitochondrial fusion

Drugs targeting TGF-β/Notch interaction attenuate hypertrophic scar formation by optic atrophy 1-mediated mitochondrial fusion

  • Mol Cell Biochem. 2023 Dec 29. doi: 10.1007/s11010-023-04912-y.
Da Huo # 1,  Xin-Yu Bi # 2,  Jun-Ling Zeng 3,  Da-Mao Dai 4,  Xiang-Lin Dong 5
Affiliations

Affiliations

  • 1 Department of Plastic and Aesthetic, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830011, Xinjiang, People's Republic of China.
  • 2 Department of Rehabilitation Medicine, The First Affiliated Hospital of China Medical University, Shenyang, 110001, Liaoning Province, People's Republic of China.
  • 3 Laboratory Animal Research Center of Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, People's Republic of China.
  • 4 Department of Plastic and Cosmetic Surgery, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, 518001, Guangdong, People's Republic of China. [email protected].
  • 5 Department of Plastic and Aesthetic, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830011, Xinjiang, People's Republic of China. [email protected].
  • # Contributed equally.
PMID: 38158493 DOI: 10.1007/s11010-023-04912-y
Abstract

Hypertrophic scar (HS) formation is a cutaneous fibroproliferative disease that occurs after skin injuries and results in severe functional and esthetic disability. To date, few drugs have shown satisfactory outcomes for the treatment of HS formation. Transforming growth factor-beta (TGF-β)/Notch interaction via small mothers against decapentaplegic 3 (SMAD3) could facilitate HS formation; therefore, targeting TGF-β/ Notch interaction via SMAD3 is a potential therapeutic strategy to attenuate HS formation. In addition, optic atrophy 1 (OPA1)-mediated mitochondrial fusion contributes to fibroblast proliferation, and TGF-β/SMAD3 axis and the Notch1 pathway facilitate OPA1-mediated mitochondrial fusion. Thus, the aim of this study was to investigate whether drugs targeting TGF-β/Notch interaction via SMAD3 suppressed fibroblast proliferation to attenuate HS formation through OPA1-mediated mitochondrial fusion. We found that the TGF-β pathway, Notch pathway, and TGF-β/Notch interaction via SMAD3 were inhibited by pirfenidone, the gamma- secretase inhibitor DAPT, and SIS3 in human keloid fibroblasts (HKF) and an HS rat model, respectively. Protein interaction was detected by co-immunoprecipitation, and mitochondrial morphology was determined by electron microscopy. Our results indicated that pirfenidone, DAPT, and SIS3 suppressed the proliferation of HKFs and attenuated HS formation in the HS rat model by inhibiting TGF-β/Notch interaction via SMAD3. Moreover, pirfenidone, DAPT, and SIS3 hindered OPA1-mediated mitochondrial fusion through inhibiting TGF-β/Notch interaction, thereby suppressing the proliferation of HS fibroblasts and HS formation. In summary, these findings investigating the effects of drugs targeting TGF-β/Notch interaction on HS formation might lead to novel drugs for the treatment of HS formation.

Keywords

DAPT; Hypertrophic scar formation; Mitochondrial fusion; Pirfenidone; SIS3; TGF-β/Notch interaction.

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