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

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.