{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T07:16:39Z","timestamp":1793085399564,"version":"4.5.0"},"reference-count":29,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T00:00:00Z","timestamp":1784678400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pediatr."],"abstract":"<jats:p>Infantile hemangioma (IH) follows a characteristic clinical course, yet the mechanisms that sustain rapid postnatal growth and later permit fibrofatty regression remain incompletely resolved. This gap has practical consequences, because some lesions threaten function, some respond incompletely to propranolol, and residual tissue change can remain important after growth arrest. Recent studies have expanded the field beyond classical angiogenic signaling to include phase-specific cell states, macrophage-endothelial crosstalk, and endothelial metabolism, but these advances are usually discussed separately. In this review, we prioritize human lesion tissue, patient-linked phase-resolved data, and primary hemangioma endothelial cell (HemEC)\/hemangioma stem cell (HemSC) studies, while using cell-line and xenograft systems mainly for mechanistic dissection. Across these evidence tiers, the evidence points to a phase-linked model. Proliferative IH is supported by reciprocal signaling among hemangioma stem cells, endothelial cells, mural cells, and activated macrophages; enhanced glycolysis and selective amino acid use sustain endothelial growth; M2-skewed macrophage signals promote endothelial proliferation and differentiation; and HemSC-derived cues protect macrophages from ferroptosis through NRF2-GPX4. Involution appears to involve loss of this supportive niche, increased lipid peroxidation, and cell-state shifts that permit mesenchymal and adipogenic differentiation. However, endothelial-to-mesenchymal transition should not be treated as uniformly regressive: inflammatory EndMT linked to M1 cytokines differs from TGF-\u03b21-driven programs that can still enhance migration and angiogenesis. That distinction is relevant for biomarker design and therapeutic targeting. We argue that the most informative next steps are phase-resolved human cohorts, spatial validation of macrophage and endothelial states, and early translational studies that pair standard therapy with rational inhibitors of glycolysis, PI3K\/AKT\/mTOR signaling, or macrophage survival pathways.<\/jats:p>","DOI":"10.3389\/fped.2026.1847957","type":"journal-article","created":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T13:44:07Z","timestamp":1784727847000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Determinants of proliferation and involution in infantile hemangioma: macrophage crosstalk, endothelial plasticity, and metabolic rewiring"],"prefix":"10.3389","volume":"14","author":[{"given":"Beichen","family":"Cai","sequence":"first","affiliation":[{"name":"Department of Plastic Surgery, The First Affiliated Hospital of Fujian Medical University","place":["Fuzhou, China"]},{"name":"Department of Plastic 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China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Plastic Surgery, The First Affiliated Hospital of Fujian Medical University","place":["Fuzhou, China"]},{"name":"Department of Plastic Surgery, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital of Fujian Medical University","place":["Fuzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaofen","family":"Wan","sequence":"additional","affiliation":[{"name":"Department of Plastic Surgery, The First Affiliated Hospital of Fujian Medical University","place":["Fuzhou, China"]},{"name":"Department of Plastic Surgery, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital of Fujian Medical University","place":["Fuzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuejun","family":"Ni","sequence":"additional","affiliation":[{"name":"Department of Plastic Surgery, The First Affiliated Hospital of Fujian Medical University","place":["Fuzhou, China"]},{"name":"Department of Plastic Surgery, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital of Fujian Medical University","place":["Fuzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiuying","family":"Shan","sequence":"additional","affiliation":[{"name":"Department of Plastic Surgery, The First Affiliated Hospital of Fujian Medical University","place":["Fuzhou, China"]},{"name":"Department of Plastic Surgery, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital of Fujian Medical University","place":["Fuzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Biao","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Plastic Surgery, The First Affiliated Hospital of Fujian Medical University","place":["Fuzhou, China"]},{"name":"Department of Plastic Surgery, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital of Fujian Medical University","place":["Fuzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,22]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"e20183475","DOI":"10.1542\/peds.2018-3475","article-title":"Clinical practice guideline for the management of infantile hemangiomas","volume":"143","author":"Krowchuk","year":"2019","journal-title":"Pediatrics"},{"key":"B2","doi-asserted-by":"publisher","first-page":"735","DOI":"10.1056\/NEJMoa1404710","article-title":"A randomized, controlled trial of oral propranolol in 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