PURPOSE: Benign fibroproliferative disorders known as keloids feature excessive fibroblast proliferation coupled with collagen accumulation, yet effective treatment remains lacking. Enhancer of zeste homolog 2 (EZH2) is involved in various skin diseases involving cell hyperproliferation; however, uncertainty persists regarding EZH2's specific role in driving keloid formation. Focusing on keloid pathogenesis, this research delineates EZH2-mediated proliferative mechanisms in keloid fibroblasts (KFs). MATERIALS AND METHODS: We examined EZH2 expression in KFs compared to normal human skin fibroblasts (HDFs). After knocking down EZH2 in KFs, CCK-8 assay for cell growth, along with EdU staining, and apoptosis was quantified through a combination of flow cytometry and Western blotting, migration was evaluated with a scratch assay, and matrix remodeling was analyzed through Western blot and immunofluorescence detection of collagen I/III, MMP-1/3, and α-SMA. Lipid ROS, thiobarbituric acid reactive substances (TBARS), and alongside quantification of core ferroptosis-associated mediators, with ferrostatin-1 (Fer-1) used for rescue experiments. RESULTS: EZH2 expression was markedly elevated in KFs compared to HDFs. Knocking down EZH2 suppressed KF proliferation, migration, and collagen deposition, while promoting apoptosis and triggering ferroptosis, as indicated by increased lipid ROS and iron levels. Fer-1 treatment partially negated these outcomes, lessening the effects of EZH2 knockdown on fibroblast function and extracellular matrix dynamics. CONCLUSIONS: EZH2 is highly expressed in KFs and regulates KFs' hyperproliferation and collagen deposition partially through inhibiting ferroptosis, suggesting EZH2 as a potential therapeutic target for keloids.
Yang et al. (Thu,) studied this question.
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