Liu Jingjing, Zhong Wenqun, Wang Rong, Wang Peipei, Tong Guoyong, Chai Maosheng, Sun Yu, Zhu Tianshuang, Huang Congfa, Yang Shaodong, Zhou Xiaoshun, Mou Dongsheng, Cai Yu
State Key Laboratory of Oral and Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School and Hospital of Stomatology Wuhan University Wuhan China.
Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology Wuhan University Wuhan China.
J Am Heart Assoc. 2025 Jan 7;14(1):e034261. doi: 10.1161/JAHA.124.034261. Epub 2024 Dec 20.
Ferroptosis is a programmed cell death caused by iron-dependent accumulation and cellular lipid peroxides, which is different from apoptosis and pyroptosis. This study investigated the possible effect of ferroptotic response in the pathogenesis of infantile hemangioma (IH).
The staining level of 4-hydroxynonenal (4-HNE), the marker of ferroptotic cells, was significantly increased in the involutive IH samples compared with the proliferative samples (9 proliferative versus 12 involutive lesions, =0.0152). By contrast, the expression of glutathione peroxidase 4 (GPX4), a key enzyme regulating ferroptotic resistance, was significantly increased in the involutive IH samples. Meanwhile, the GPX4 was richly expressed in macrophages of IH. The data from in vitro study showed that the mRNA (=0.0002) and protein (=0.0385) expression levels of GPX4 were significantly upregulated in macrophages cultured with hemangioma-derived stem cells conditional medium (HemSC-CM). Mechanistically, HemSC-CM promoted the expression of GPX4 in macrophages (=0.0482) by increasing nuclear factor erythroid 2-related factor 2 translocation to the nucleus (=0.0026). Additionally, inhibition of GPX4 or inducing ferroptosis in macrophages could inhibit progression of lesion in IH nude mice mode.
Hemangioma-derived stem cells (HemSCs) could promote macrophage ferroptotic resistance through upregulating expression of GPX4, which is required for the progression of IH.
铁死亡是一种由铁依赖性积累和细胞脂质过氧化物引起的程序性细胞死亡，与细胞凋亡和焦亡不同。本研究探讨了铁死亡反应在婴儿血管瘤（IH）发病机制中的可能作用。
与增殖期样本相比，消退期IH样本中铁死亡细胞标志物4-羟基壬烯醛（4-HNE）的染色水平显著升高（9个增殖期病变与12个消退期病变，P = 0.0152）。相比之下，消退期IH样本中调节铁死亡抗性的关键酶谷胱甘肽过氧化物酶4（GPX4）的表达显著增加。同时，GPX4在IH的巨噬细胞中大量表达。体外研究数据显示，在用血管瘤来源的干细胞条件培养基（HemSC-CM）培养的巨噬细胞中，GPX4的mRNA（P = 0.0002）和蛋白质（P = 0.0385）表达水平显著上调。机制上，HemSC-CM通过增加核因子红细胞2相关因子2向细胞核的转位（P = 0.0026）来促进巨噬细胞中GPX4的表达（P = 0.0482）。此外，抑制GPX4或诱导巨噬细胞铁死亡可抑制IH裸鼠模型中病变的进展。
血管瘤来源的干细胞（HemSCs）可通过上调GPX4的表达来促进巨噬细胞的铁死亡抗性，而GPX4是IH进展所必需的。
