Multidimensional analysis of the pathological mechanisms of infantile hemangioma: metabolic reprogramming, immune remodeling, and programmed cell death

Infantile hemangioma (IH) is a common benign vascular tumor of infancy. Its self-limiting course, which progresses from proliferation to involution, involves aberrant angiogenesis, altered cell fate, and remodeling of the lesional microenvironment. Hypoxia/HIF-VEGF, PI3K/AKT, MAPK/ERK, and Notch signaling pathways contribute to vascular formation and cellular differentiation. During the proliferative phase, hemangioma endothelial cells (HemECs) undergo metabolic reprogramming characterized by enhanced glycolysis and altered amino acid metabolism, including pathways involving glutamine, arginine, glycine, and serine. Macrophages, mast cells, T cells, and their associated cytokines also shape a proangiogenic immune microenvironment. During the involuting phase, the transition of hemangioma stem cells (HemSCs) toward an adipogenic fate, together with changes in lesional cell composition, contributes to fibrofatty tissue remodeling. At the same time, the immune microenvironment undergoes stage-dependent remodeling, and processes related to programmed cell death, including apoptosis, pyroptosis, necroptosis, ferroptosis, and autophagy, change accordingly. However, the strength of evidence supporting these processes in IH varies. Current studies have identified specific links among metabolism, immunity, and cell death, but they have not established a fixed, sequential causal cascade; PANoptosis remains an unverified mechanistic hypothesis in IH. Although propranolol is the first-line treatment, variable treatment responses, rebound growth after treatment withdrawal, and refractory lesions remain clinical challenges. Focusing on the transition from proliferation to involution, this review integrates current evidence and potential mechanistic connections to inform research on spontaneous involution and the development of interventions tailored to specific disease stages and cell types.