Promoting ferroptosis of keloid fibroblasts: a key mechanism underlying the efficacy of 5-aminolevulinic acid photodynamic therapy for keloids

IF 2.6 3区医学 Q2 ONCOLOGY

Photodiagnosis and Photodynamic Therapy Pub Date : 2025-07-26 DOI:10.1016/j.pdpdt.2025.104736

Jiaying Zhang , Yahui Feng , Ning Zhang , Xiaoqing Wang , Dongmei Li , Dongmei Shi

{"title":"Promoting ferroptosis of keloid fibroblasts: a key mechanism underlying the efficacy of 5-aminolevulinic acid photodynamic therapy for keloids","authors":"Jiaying Zhang , Yahui Feng , Ning Zhang , Xiaoqing Wang , Dongmei Li , Dongmei Shi","doi":"10.1016/j.pdpdt.2025.104736","DOIUrl":null,"url":null,"abstract":"<div><h3>Objective</h3><div>This study aims to evaluate the efficacy of 5-aminolevulinic acid photodynamic therapy (ALA-PDT) for keloid treatment and explore its molecular mechanisms.</div></div><div><h3>Methods</h3><div>Nine keloid patients were enrolled between May 2024 and March 2025. All patients received ALA-PDT, with therapeutic efficacy systematically evaluated for keloid lesions. Keloid fibroblasts (KFs) isolated from lesions were subsequently treated with ALA-PDT. Mitochondrial dehydrogenase activity, collagen metabolism, and matrix metalloproteinase (MMP) expression were assessed in KFs at gene and protein levels. Reactive oxygen species (ROS) production and ferroptosis-associated molecular expression in ALA-PDT-treated KFs were also investigated to explore molecular mechanisms.</div></div><div><h3>Results</h3><div>Clinically, four sessions of ALA-PDT (administered at 14-day intervals) reduced keloid lesion volume by 45 %. Histopathological analysis showed significant collagen architecture remodeling. ALA-PDT disrupted keloid fibroblasts ultrastructure, evidenced by mitochondrial swelling, autophagosome formation, and membrane blebbing, with a 3.2-fold increase in morphological changes post-treatment. The inhibitory effect of ALA-PDT on KFs mitochondrial dehydrogenase activity was ALA dose-dependent. Mechanistically, ALA-PDT inhibited collagen expression via MMP upregulation. Additionally, ALA-PDT directly induced ferroptosis in KFs, evidenced by characteristic structural destruction. Further studies showed ALA-PDT significantly activated the ferroptosis signaling pathway in KFs, modulating key molecules (GPX4, ACSL4, NOX-1, SLC7A11, NCOA4). ALA-PDT also upregulated ferroptosis-associated factors (MMP-9, MMP-1, CCL-2), promoted ROS production, and induced ferroptosis in KFs.</div></div><div><h3>Conclusion</h3><div>ALA-PDT provides an effective and safe keloid treatment. Its mechanism involves inducing ferroptosis via ROS production and modulating the extracellular matrix to restore collagen balance. By selectively targeting KFs while sparing normal fibroblasts, ALA-PDT demonstrates remarkable therapeutic precision.</div></div>","PeriodicalId":20141,"journal":{"name":"Photodiagnosis and Photodynamic Therapy","volume":"55 ","pages":"Article 104736"},"PeriodicalIF":2.6000,"publicationDate":"2025-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Photodiagnosis and Photodynamic Therapy","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S1572100025002686","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"ONCOLOGY","Score":null,"Total":0}

引用次数: 0

Abstract

Objective

This study aims to evaluate the efficacy of 5-aminolevulinic acid photodynamic therapy (ALA-PDT) for keloid treatment and explore its molecular mechanisms.

Methods

Nine keloid patients were enrolled between May 2024 and March 2025. All patients received ALA-PDT, with therapeutic efficacy systematically evaluated for keloid lesions. Keloid fibroblasts (KFs) isolated from lesions were subsequently treated with ALA-PDT. Mitochondrial dehydrogenase activity, collagen metabolism, and matrix metalloproteinase (MMP) expression were assessed in KFs at gene and protein levels. Reactive oxygen species (ROS) production and ferroptosis-associated molecular expression in ALA-PDT-treated KFs were also investigated to explore molecular mechanisms.

Results

Clinically, four sessions of ALA-PDT (administered at 14-day intervals) reduced keloid lesion volume by 45 %. Histopathological analysis showed significant collagen architecture remodeling. ALA-PDT disrupted keloid fibroblasts ultrastructure, evidenced by mitochondrial swelling, autophagosome formation, and membrane blebbing, with a 3.2-fold increase in morphological changes post-treatment. The inhibitory effect of ALA-PDT on KFs mitochondrial dehydrogenase activity was ALA dose-dependent. Mechanistically, ALA-PDT inhibited collagen expression via MMP upregulation. Additionally, ALA-PDT directly induced ferroptosis in KFs, evidenced by characteristic structural destruction. Further studies showed ALA-PDT significantly activated the ferroptosis signaling pathway in KFs, modulating key molecules (GPX4, ACSL4, NOX-1, SLC7A11, NCOA4). ALA-PDT also upregulated ferroptosis-associated factors (MMP-9, MMP-1, CCL-2), promoted ROS production, and induced ferroptosis in KFs.

Conclusion

ALA-PDT provides an effective and safe keloid treatment. Its mechanism involves inducing ferroptosis via ROS production and modulating the extracellular matrix to restore collagen balance. By selectively targeting KFs while sparing normal fibroblasts, ALA-PDT demonstrates remarkable therapeutic precision.

查看原文本刊更多论文

促进瘢痕疙瘩成纤维细胞铁下垂：5-氨基乙酰丙酸光动力治疗瘢痕疙瘩疗效的关键机制。

目的：评价5-氨基乙酰丙酸光动力疗法（ALA-PDT）治疗瘢痕疙瘩的疗效，并探讨其分子机制。方法：在2024年5月至2025年3月期间招募9例瘢痕疙瘩患者。所有患者均接受ALA-PDT治疗，系统评估瘢痕疙瘩病变的治疗效果。从病变中分离的瘢痕疙瘩成纤维细胞（KFs）随后用ALA-PDT治疗。在基因和蛋白水平上评估KFs的线粒体脱氢酶活性、胶原代谢和基质金属蛋白酶（MMP）表达。我们还研究了ala - pdt处理的KFs中活性氧（ROS）的产生和死铁相关的分子表达，以探索其分子机制。结果：在临床上，四次ALA-PDT（每隔14天给药）使瘢痕疙瘩的体积减少了45%。组织病理学分析显示明显的胶原结构重塑。ALA-PDT破坏瘢痕疙瘩成纤维细胞超微结构，表现为线粒体肿胀、自噬体形成和膜起泡，处理后形态学改变增加3.2倍。ALA- pdt对KFs线粒体脱氢酶活性的抑制作用呈ALA剂量依赖性。在机制上，ALA-PDT通过上调MMP抑制胶原表达。此外，ALA-PDT直接诱导KFs的铁下垂，表现为特征性的结构破坏。进一步的研究表明，ALA-PDT通过调节关键分子（GPX4、ACSL4、NOX-1、SLC7A11、NCOA4），显著激活KFs中的铁死亡信号通路。ALA-PDT还上调铁下垂相关因子（MMP-9、MMP-1、CCL-2），促进ROS的产生，并诱导KFs中的铁下垂。结论：ALA-PDT治疗瘢痕疙瘩安全有效。其机制包括通过ROS产生诱导铁下垂和调节细胞外基质以恢复胶原平衡。ALA-PDT通过选择性靶向KFs而保留正常成纤维细胞，显示出显著的治疗精度。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Photodiagnosis and Photodynamic Therapy ONCOLOGY-

CiteScore

5.80

自引率

24.20%

发文量

509

审稿时长

50 days

期刊介绍： Photodiagnosis and Photodynamic Therapy is an international journal for the dissemination of scientific knowledge and clinical developments of Photodiagnosis and Photodynamic Therapy in all medical specialties. The journal publishes original articles, review articles, case presentations, "how-to-do-it" articles, Letters to the Editor, short communications and relevant images with short descriptions. All submitted material is subject to a strict peer-review process.