BACKGROUND: 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). METHODS AND RESULTS: 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, P=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 (P=0.0002) and protein (P=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 (P=0.0482) by increasing nuclear factor erythroid 2-related factor 2 translocation to the nucleus (P=0.0026). Additionally, inhibition of GPX4 or inducing ferroptosis in macrophages could inhibit progression of lesion in IH nude mice mode. CONCLUSIONS: Hemangioma-derived stem cells (HemSCs) could promote macrophage ferroptotic resistance through upregulating expression of GPX4, which is required for the progression of IH.