Fibroblast adipogenesis restricts hemangioma growth through a PPARγ/Hippo-YAP/TAZ axis that promotes endothelial apoptosis and cell cycle arrest

Infantile hemangioma (HEM) is the most common benign vascular tumor in infancy and is characterized by a unique progression pattern involving rapid proliferation followed by spontaneous involution. Increasing evidence suggests that the tumor microenvironment plays a critical role in regulating endothelial cell behavior during HEM development. In this study, we investigated how fibroblast (FB) phenotypic remodeling influences hemangioma endothelial cell (HemEC) function. Through single-cell RNA sequencing analysis, we identified extensive communication between FBs and ECs within HEM tissues. Functional experiments revealed that adipogenically differentiated FBs markedly suppressed HemEC proliferation, migration, invasion, and tube formation while promoting apoptosis. Transcriptomic analysis further demonstrated that this inhibitory effect was mediated by activation of the Hippo-YAP/TAZ signaling pathway in ECs. Mechanistically, adipogenic differentiation significantly upregulated PPARG expression in FBs, which in turn triggered Hippo pathway activation in ECs, leading to YAP/TAZ phosphorylation and nuclear exclusion. Importantly, PPARG silencing in FBs or pharmacological inhibition of the Hippo pathway reversed these effects. Collectively, our findings reveal a previously unrecognized microenvironmental regulatory mechanism in which PPARγ-driven fibroblast adipogenesis suppresses HEM progression through activation of the Hippo-YAP/TAZ pathway in endothelial cells. This study provides new insights into stromal-endothelial communication in HEM and suggests that the PPARγ-Hippo signaling axis may represent a potential therapeutic target.Proposed molecular mechanism by which PPARγ-mediated FB adipogenic differentiation regulates Hippo-YAP/TAZ signaling activity in HemECs. Note: Created in Biorender.