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

## TL;DR

This study shows that Epiregulin (EREG) causes skin reactions in patients taking sorafenib, suggesting that blocking EREG could help reduce these side effects.

## Contribution

The study is the first to link EREG to sorafenib-induced skin reactions and proposes EREG as a therapeutic target.

## Key findings

- EREG promotes keratinocyte proliferation in HaCaT cells (p < 0.05).
- Sorafenib-treated mice show HFSR features like erythema and hyperkeratosis (p < 0.001).
- EREG expression is significantly upregulated in HFSR-affected tissues (p < 0.001).

## Abstract

•First evidence linking EREG to sorafenib-induced HFSR via keratinocyte proliferation.•Mouse model recapitulates human HFSR with neutrophil-rich inflammation and hyperkeratosis.•EREG promotes HaCaT proliferation (p < 0.05), while sorafenib acts indirectly.•100 mg/kg sorafenib in mice (≈10 mg/kg human dose) validated by FDA scaling.•Therapeutic potential: EREG blockade may mitigate HFSR severity.

First evidence linking EREG to sorafenib-induced HFSR via keratinocyte proliferation.

Mouse model recapitulates human HFSR with neutrophil-rich inflammation and hyperkeratosis.

EREG promotes HaCaT proliferation (p < 0.05), while sorafenib acts indirectly.

100 mg/kg sorafenib in mice (≈10 mg/kg human dose) validated by FDA scaling.

Therapeutic potential: EREG blockade may mitigate HFSR severity.

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.

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).

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.

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.