Human adipose mesenchymal stem cell-derived exosomes alleviate fibrosis by restraining ferroptosis in keloids

• Published in: Frontiers in pharmacology Vol. 15; p. 1431846
• Main Authors: Tian, Yuan, Li, Meijia, Cheng, Rong, Chen, Xinyue, Xu, Zhishan, Yuan, Jian, Diao, Zhiyong, Hao, Lijun
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 2024
• Subjects: adipose-derived mesenchymal stem cells; extracellular vesicles; ferritic; fibrosis; GPx4; ferritic; fibrosis; extracellular vesicles; GPx4; adipose-derived mesenchymal stem cells
• ISSN: 1663-9812; 1663-9812
• DOI: 10.3389/fphar.2024.1431846

Keloid is a fibroproliferative disease with unsatisfactory therapeutic effects and a high recurrence rate. exosomes produced by adipose-derived mesenchymal stem cells (ADSC-Exos) have attracted significant interest due to their ability to treat fibrosis. However, the molecular mechanisms of ADSC-Exos in keloids remain inconclusive. Our study revealed the relationship between ferroptosis and fibrosis in keloids. Subsequently, this study aimed to explore further the anti-fibrotic effect of ADSC-Exos on keloids through ferroptosis and the potential underlying mechanisms. To investigate the impact of ferroptosis on keloid fibrosis, Erastin and ferrostatin-1 (fer-1) were utilized to treat keloid fibroblast. Keloid keloids treated with Erastin and fer-1 were cocultured with ADSC-Exos to validate the impact of ferroptosis on the effect of ADSC-Exos on keloid anti-ferrotic protein, peroxidase 4 (GPX4) and anti-fibrotic effects and by Western blot, as well as variations in iron metabolite expression, malondialdehyde (MDA), liposomal peroxidation (LPO) and glutathione (GSH) were analyzed. The effect of solute carrier family 7-member 11 (SLC7A11) silencing on ADSC-Exo-treated keloid fibroblast was investigated. Iron metabolite dysregulation was validated in keloids. Fibrosis progression is enhanced by Erastin-induced ferroptosis. The anti-fibrotic effects of ADSC-Exos and fer-1 are related to their ability to prevent iron metabolism. ADSC-Exos effectively suppressed keloid fibrosis progression and increased GSH and GPX4 gene expression. Additionally, the use of Erastin limits the effect of ADSC-Exos in keloids. Furthermore, the effect of ADSC-Exos on keloids was associated with SLC7A11-GPX4 signaling pathway. We demonstrated a new potential mechanism by which anti-ferroptosis inhibits the progression of keloid fibrosis and identified an ADSC-Exo-based keloid therapeutic strategy. Resisting the occurrence of ferroptosis and the existence of the SLC7A11-GPX4 signaling pathway might serve as a target for ADSC-Exos.