ArticleCell research2020
s-HBEGF/SIRT1 circuit-dictated crosstalk between vascular endothelial cells and keratinocytes mediates sorafenib-induced hand-foot skin reaction that can be reversed by nicotinamide.
Article in Cell research, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 43 citations in OpenAlex.
- Prophylactic effect of the traditional Chinese medicine formulaFrontiers in pharmacology · 2025Trial
- The Efficacy and Safety of the Shouzu Ning Decoction Treatment Versus Halometasone Plus Celecoxib Treatment in Patients With Grade 2 HFSR: A Randomized Clinical Trial.Integrative cancer therapiesTrial
- Liver-originated selective autophagy of BTD by alectinib underlies concurrent hepatotoxicity and dermatotoxicity.Autophagy · 2026Article
- Transforming a Roadblock into a Roadmap: Evolving HFSR Management From Adverse Event to Efficacy Biomarker.Current treatment options in oncology · 2026Review
- The advantages and challenges of sorafenib combination therapy: Drug resistance, toxicity and future directions (Review).Oncology letters · 2025Review
- Helicobacter pylori CagA elevates FTO to induce gastric cancer progression via a "hit-and-run" paradigm.Cancer communications (London, England) · 2025Article
- Endothelium-specific sensing of mechanical signals drives epidermal aging through coordinating retinoid metabolism.Theranostics · 2025Article
- Isopentyl-Deoxynboquinone Induces Mitochondrial Dysfunction and G2/M Phase Cell Cycle Arrest to Selectively KillAntioxidants & redox signaling · 2024Article
- A Potential Association of Zinc Deficiency and Tyrosine Kinase Inhibitor-Induced Hand-Foot Skin Reaction.Biological trace element research · 2023Review
- Knockdown of TACC3 inhibits tumor cell proliferation and increases chemosensitivity in pancreatic cancer.Cell death & disease · 2023Article
- Protective effect of borneol on the cutaneous toxicity of gilteritinib.Zhejiang da xue xue bao. Yi xue ban = Journal of Zhejiang University. Medical sciences · 2023Article
- Clinical characteristics, treatment outcomes, and prognosis in patients with MKIs-associated hand-foot skin reaction: a retrospective study.Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer · 2023Article
- A Review of Bullous Dermatologic Adverse Events Associated with Anti-Cancer Therapy.Biomedicines · 2023Review
- 3D bioprinting of an implantable xeno-free vascularized human skin graft.Bioengineering & translational medicine · 2023Article
- Identification of Potential Predictors of Prognosis and Sorafenib-Associated Survival Benefits in Patients with Hepatocellular Carcinoma after Transcatheter Arterial Chemoembolization.Current oncology (Toronto, Ont.) · 2022Article
- Extracellular Vesicles Derived from SIPA1Biology · 2022Article
- Article
- Identification ofAntioxidants (Basel, Switzerland) · 2021Article
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Authors and funding
14 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Hand-foot skin reaction (HFSR), among the most significant adverse effects of sorafenib, has been limiting the clinical benefits of this frontline drug in treating various malignant tumors. The mechanism underlying such toxicity remains poorly understood, hence the absence of effective intervention strategies. In the present study, we show that vascular endothelial cells are the primary cellular target of sorafenib-induced HFSR wherein soluble heparin-binding epidermal growth factor (s-HBEGF) mediates the crosstalk between vascular endothelial cells and keratinocytes. Mechanistically, s-HBEGF released from vascular endothelial cells activates the epidermal growth factor receptor (EGFR) on keratinocytes and promotes the phosphorylation of c-Jun N-terminal kinase 2 (JNK2), which stabilizes sirtuin 1 (SIRT1), an essential keratinization inducer, and ultimately gives rise to HFSR. The administration of s-HBEGF in vivo could sufficiently induce hyper-keratinization without sorafenib treatment. Furthermore, we report that HBEGF neutralization antibody, Sirt1 knockdown, and a classic SIRT1 inhibitor nicotinamide could all significantly reduce the sorafenib-induced HFSR in the mouse model. It is noteworthy that nicotinic acid, a prodrug of nicotinamide, could substantially reverse the sorafenib-induced HFSR in ten patients in a preliminary clinical study. Collectively, our findings reveal the mechanism of vascular endothelial cell-promoted keratinization in keratinocytes and provide a potentially promising therapeutic strategy for the treatment of sorafenib-induced HFSR.
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