In the ever-evolving landscape of pediatric vascular anomalies, infantile hemangioma (IH) stands as the most common benign tumor affecting infants worldwide. Despite its benign nature, the rapid proliferation and potential complications associated with IH present significant clinical challenges. Propranolol (PRN), a non-selective beta-adrenergic receptor blocker, has revolutionized the treatment of IH since its serendipitous discovery as an effective therapy over a decade ago. However, puzzling aspects remain surrounding its mechanism of action, and clinical hurdles such as drug resistance and rebound growth upon cessation of therapy continue to perplex clinicians. A groundbreaking study led by Zhu et al. has taken a significant step toward decoding these mysteries, unveiling critical insights into how propranolol drives IH regression at a cellular and molecular level.
Historically, the precise biological pathways through which propranolol exerts its therapeutic effects on IHs have been elusive. This new research addresses these gaps by focusing on the behavior of hemangioma stem cells (HemSCs), which are believed to be the progenitor cells driving both the vasculogenic proliferation and involution phases of these tumors. The study sheds light on how propranolol influences HemSCs by modulating metabolic pathways, specifically glycolysis, which is foundational for cellular energy generation and differentiation. The researchers pinpointed that propranolol suppresses hexokinase 2 (HK2), a key enzyme catalyzing the first step of glycolysis, thereby altering the fate of these stem cells.
By dampening HK2 activity, propranolol effectively disrupts glycolytic flux within HemSCs, which results in two intriguing outcomes: acceleration of adipogenesis and inhibition of endothelial differentiation. Adipogenesis is the process through which precursor cells develop into adipocytes, or fat cells, a hallmark of the natural involution phase of hemangiomas. Conversely, endothelial differentiation fosters the formation of new blood vessels, fueling tumor growth. The study’s findings suggest that propranolol shifts the balance toward fat cell development, promoting regression of the hemangioma by curtailing its vascular supply and encouraging tissue remodeling.
This metabolic checkpoint role of HK2 in HemSC differentiation is a revelation with profound therapeutic implications. The inhibition of glycolysis as a driver of tissue remodeling redefines our understanding of propranolol’s pharmacodynamics beyond its classic beta-adrenergic blockade. Such insights illuminate why resistance and rebound phenomena might occur in clinical settings; if HemSCs adapt to maintain glycolytic capacity despite propranolol treatment, the suppressive effect on endothelial formation could diminish, allowing resurgence of the tumor.
The study leverages advanced cellular assays and metabolic analyses to characterize HemSC responses under propranolol exposure. Using meticulous in vitro models, the researchers assessed enzymatic activity, gene expression patterns, and lineage markers that signify cell fate commitment. Their data demonstrate a clear suppression of HK2 protein levels and glycolytic intermediates, correlating robustly with enhanced lipid droplet formation indicative of accelerated adipogenesis. These cellular shifts collectively converge to reduce the proliferative and angiogenic potential of the hemangioma stem cells.
Furthermore, the research delves into signaling cascades downstream of metabolic reprogramming. The suppression of HK2 alters the availability of critical substrates required for biosynthetic pathways, which are essential for supporting the rapid expansion of endothelial progenitors. This metabolic bottleneck effectively stymies the neovascularization process, providing a coherent explanation for the clinical efficacy of propranolol in halting IH progression. The knit between metabolism and differentiation unveiled here points toward a rich therapeutic target landscape for future interventions.
Clinically, these findings open avenues to enhance treatment strategies for IH, especially in cases where resistance to propranolol arises or where rebound phenomena post-treatment discontinuation are observed. By identifying HK2-mediated glycolysis as an axis of vulnerability, adjunct therapies that more precisely target metabolic pathways may be developed to potentiate propranolol’s effects or overcome its limitations. Moreover, therapeutic monitoring of metabolic markers could provide predictive insights into patient responsiveness, tailoring personalized treatment regimens.
This new mechanistic insight also challenges the previously held notion that propranolol’s benefits stem solely from hemodynamic and vasoconstrictive effects. Instead, it paints a more comprehensive picture where cellular metabolism and differentiation programs are central. This expands the horizon for research into other beta-blockers or metabolic modulators as alternative or complementary therapies for IH and possibly other vascular tumors.
Given the pivotal role of glycolysis in diverse cancers and rapidly dividing cells, the implications of this research may transcend pediatric hemangiomas. Targeting metabolic enzymes such as HK2 holds promise not only for vascular anomalies but also for malignancies exhibiting metabolic dysregulation. The study’s integrative approach combining stem cell biology, metabolic biochemistry, and pharmacology exemplifies the kind of interdisciplinary research required to unravel complex disease mechanisms.
Importantly, the paper emphasizes the delicate balance between quiescence and proliferation maintained by HemSCs, governed in part by metabolic cues. Propranolol’s capacity to tilt this balance underscores a broader principle that metabolic modulation can govern cellular identity and fate decisions. This concept echoes across stem cell biology and regenerative medicine, where fine-tuning metabolism could direct tissue repair, pathology, or remodeling.
As the first-line treatment, propranolol’s widespread adoption demands continuous efforts to optimize its use and understand its failings. The elucidation of HK2’s role offers a promising biomarker for monitoring therapy and a novel intervention point to mitigate relapse. Future clinical trials incorporating metabolic agents could validate these preclinical findings and refine treatment protocols, improving long-term outcomes for infants with IH.
This study’s methodological rigor, combined with its clinical relevance, sets a new benchmark for research into IH treatment mechanisms. The integration of metabolic assays with functional differentiation studies provides robust evidence supporting a central role for glycolysis inhibition in propranolol-driven regression. This paradigm shift redefines our approach toward pediatric vascular tumors, underlining the need for combining metabolic and pharmacological insights for therapeutic innovation.
Finally, the research invites a broader reflection on drug repurposing strategies. Propranolol, a decades-old cardiovascular drug, through its unexpected modulation of stem cell metabolism and differentiation, exemplifies the untapped potential lying within established medications. This discovery not only enriches our armamentarium against IH but also encourages revisiting old drugs through new scientific lenses to uncover hidden therapeutic mechanisms.
In summary, Zhu and colleagues provide compelling and transformative evidence that propranolol accelerates adipogenic differentiation while inhibiting endothelial lineage commitment of hemangioma stem cells by suppressing HK2-mediated glycolysis. This metabolic intervention orchestrates the regression of IH and contextualizes clinical challenges such as drug resistance and rebound growth. Their work unlocks a new metabolic dimension in beta-blocker therapy, heralding innovative possibilities to refine and augment treatment of infantile hemangioma and potentially other proliferative vascular pathologies.
Subject of Research: Mechanisms underlying propranolol-induced regression of infantile hemangioma via metabolic modulation of hemangioma stem cells.
Article Title: Propranolol accelerates adipogenesis and inhibits endothelium differentiation of HemSCs via suppressing HK2 mediated glycolysis.
Article References:
Zhu, T., Wang, P., Wang, R. et al. Propranolol accelerates adipogenesis and inhibits endothelium differentiation of HemSCs via suppressing HK2 mediated glycolysis. Pediatr Res (2025). https://doi.org/10.1038/s41390-025-04080-3
Image Credits: AI Generated
