Epiregulin drives keratinocyte hyperproliferation in sorafenib-induced hand-foot skin reaction: A mechanistic and therapeutic insight.

Abstract

PURPOSE: Sorafenib-induced Hand-Foot Skin Reaction (HFSR) significantly impairs patient quality of life, yet its underlying mechanisms remain poorly understood. This study investigates the pivotal role of Epiregulin (EREG), an Epidermal Growth Factor Receptor (EGFR) ligand, in driving keratinocyte hyperproliferation and the pathogenesis of HFSR. METHODS: The authors established a murine HFSR model using oral sorafenib (100 mg/kg) and analyzed paw tissues for histopathological changes (H&E staining) and EREG expression (immunohistochemistry). In vitro, HaCaT keratinocytes were treated with sorafenib and recombinant EREG to assess proliferation (CCK-8 assay). RESULTS: Sorafenib-treated mice exhibited hallmark HFSR features, including erythema, neutrophil infiltration, and thickened keratin layers (p < 0.001). EREG expression was markedly upregulated in affected tissues (p < 0.001). Notably, recombinant EREG dose-dependently enhanced HaCaT cell proliferation (p < 0.05), while sorafenib alone showed no direct proliferative effect. CONCLUSION: The present findings identify EREG as a critical mediator of keratinocyte hyperproliferation in sorafenib-induced HFSR, offering a novel therapeutic target. Moreover, EREG expression may serve as a predictive biomarker for HFSR severity, guiding personalized prophylaxis. Clinical exploration of EREG inhibition could provide a tailored approach to alleviate HFSR, improving patient adherence and treatment outcomes.