Wang Xiuxia, Yang Yating, Zhou Xianyu, Yu Shun, Luo Xusong, Lu Lin, Gao Zhen, Yang Jun
Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200011, China.
The Affiliated Hospital of Jiangnan University, Jiangsu, China.
Cell Death Discov. 2025 Jan 16;11(1):9. doi: 10.1038/s41420-024-02257-z.
Keloid is benign skin tumor, and their curing is relatively difficult due to the unclear mechanism of formation. Inducing ferroptosis of keloid fibroblasts (KFs) may become a new method for treating keloid. Here, we discover interferon (IFN)γ could induce KFs ferroptosis through inhibiting SPOC domain-containing protein 1 (SPOCD1), serving as a mode of action for CD8T cell (CTL)-mediated keloid killing. Mechanistically, keloid IFNγ deficiency in combination with reduced DNMT3A increase the expression of SPOCD1, thereby promoting KFs' proliferation and inhibiting its ferroptosis. Moreover, keloid SPOCD1 deficiency attenuates KFs progression and extracellular matrix (ECM) deposition. Reducing IFNγ and SPOCD1 simultaneously can increase the positive rate of reactive oxygen species (ROS) and promote mitochondrial shrinkage. Ex-vivo explant keloid culture has also confirmed that the reduction of SPOCD1 helps to reduce the proliferation rate of KFs, inhibit the angiogenesis of keloid scars, and thus inhibit keloid formation. Thus, IFNγ signaling paired with SPOCD1 is a natural keloid ferroptosis promoting mechanism and a mode of action of CTLs. Targeting SPOCD1 pathway is a potential anti-keloid approach.
瘢痕疙瘩是一种良性皮肤肿瘤，由于其形成机制尚不清楚，治疗相对困难。诱导瘢痕疙瘩成纤维细胞（KFs）发生铁死亡可能成为治疗瘢痕疙瘩的新方法。在此，我们发现干扰素（IFN）γ可通过抑制含SPOC结构域蛋白1（SPOCD1）诱导KFs铁死亡，这是CD8T细胞（CTL）介导的瘢痕疙瘩杀伤作用方式。机制上，瘢痕疙瘩中IFNγ缺乏与DNMT3A减少共同作用增加SPOCD1的表达，从而促进KFs增殖并抑制其铁死亡。此外，瘢痕疙瘩中SPOCD1缺乏可减弱KFs进展和细胞外基质（ECM）沉积。同时降低IFNγ和SPOCD1可增加活性氧（ROS）阳性率并促进线粒体收缩。体外瘢痕疙瘩外植体培养也证实，SPOCD1减少有助于降低KFs增殖率，抑制瘢痕疙瘩瘢痕的血管生成，从而抑制瘢痕疙瘩形成。因此，IFNγ信号与SPOCD1配对是一种天然的瘢痕疙瘩铁死亡促进机制及CTL的作用方式。靶向SPOCD1途径是一种潜在的抗瘢痕疙瘩方法。
