Tian Yuan, Li Meijia, Cheng Rong, Chen Xinyue, Xu Zhishan, Yuan Jian, Diao Zhiyong, Hao Lijun
Plastic Surgery, Harbin Medical University, Harbin, China.
Front Pharmacol. 2024 Aug 16;15:1431846. doi: 10.3389/fphar.2024.1431846. eCollection 2024.
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.
瘢痕疙瘩是一种纤维增生性疾病，治疗效果不理想且复发率高。脂肪间充质干细胞分泌的外泌体（ADSC-Exos）因其治疗纤维化的能力而备受关注。然而，ADSC-Exos在瘢痕疙瘩中的分子机制仍不明确。
我们的研究揭示了瘢痕疙瘩中 ferroptosis 与纤维化之间的关系。随后，本研究旨在进一步探讨ADSC-Exos通过ferroptosis对瘢痕疙瘩的抗纤维化作用及其潜在机制。
为研究ferroptosis对瘢痕疙瘩纤维化的影响，使用Erastin和铁死亡抑制剂1（fer-1）处理瘢痕疙瘩成纤维细胞。将用Erastin和fer-1处理的瘢痕疙瘩与ADSC-Exos共培养，以验证ferroptosis对ADSC-Exos抗瘢痕疙瘩作用的影响，通过蛋白质免疫印迹法检测抗铁死亡蛋白、过氧化物酶4（GPX4）以及抗纤维化作用，并分析铁代谢产物表达、丙二醛（MDA）、脂质过氧化（LPO）和谷胱甘肽（GSH）的变化。研究溶质载体家族7成员11（SLC7A11）沉默对ADSC-Exo处理的瘢痕疙瘩成纤维细胞的影响。
在瘢痕疙瘩中验证了铁代谢产物失调。Erastin诱导的ferroptosis增强了纤维化进程。ADSC-Exos和fer-1的抗纤维化作用与其预防铁代谢的能力有关。ADSC-Exos有效抑制瘢痕疙瘩纤维化进程并增加GSH和GPX4基因表达。此外，使用Erastin会限制ADSC-Exos在瘢痕疙瘩中的作用。此外，ADSC-Exos对瘢痕疙瘩的作用与SLC7A11-GPX4信号通路有关。
我们证明了一种新的潜在机制，即抗铁死亡抑制瘢痕疙瘩纤维化进程，并确定了一种基于ADSC-Exos的瘢痕疙瘩治疗策略。抵抗铁死亡的发生以及SLC7A11-GPX4信号通路的存在可能是ADSC-Exos的靶点。
