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Owing to repeated wounding, inflammation and unproductive healing, RDEB patients have a 68% cumulative risk of developing life\u2010threatening cSCCs by the age of 35, and a 70% risk of death by the age of 45. Despite aggressive treatment, cSCC represents the leading cause of premature mortality in these patients, highlighting an unmet clinical need. Increasing evidence points to a role of altered metabolism in the initiation and maintenance of cSCC, making metabolism a potential therapeutic target.<\/jats:p><\/jats:sec><jats:sec><jats:title>Objectives<\/jats:title><jats:p>We sought to determine the feasibility of targeting tumour cell energetics as a strategy to selectively hinder the growth advantage of aggressive cSCC.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We evaluated the cell energetics profiles of RDEB\u2010SCC cells by analysing available gene expression data against multiple gene signatures and single\u2010gene targets linked to metabolic reprogramming. Additionally, we employed real\u2010time metabolic profiling to measure glycolysis and respiration in these cells. Furthermore, we investigated the anti\u2010neoplastic properties of the metformin against human and murine high\u2010risk cSCCs in vitro and in vivo.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Gene expression analyses highlighted a divergence in cell energetics profiles between RDEB\u2010SCC and non\u2010malignant RDEB keratinocytes, with tumour cells demonstrating enhanced respiration and glycolysis scores. Real\u2010time metabolic profiling supported these data and additionally highlighted a metabolic plasticity of RDEB\u2010SCC cells. Against this background, metformin exerted an anti\u2010neoplastic potential by hampering both respiration and glycolysis, and by inhibiting proliferation in vitro. Metformin treatment in an analogous model of fast\u2010growing murine cSCC resulted in delayed tumour onset and slower tumour growth, translating to a 29% increase in median overall survival.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our data indicate that metformin exerts anti\u2010neoplastic properties in aggressive cSCCs that exhibit high\u2010risk features by interfering with respiration and glycolytic processes.<\/jats:p><\/jats:sec>","DOI":"10.1111\/jdv.19488","type":"journal-article","created":{"date-parts":[[2023,9,6]],"date-time":"2023-09-06T00:19:00Z","timestamp":1693959540000},"page":"112-123","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Metformin shows anti\u2010neoplastic properties by inhibition of oxidative phosphorylation and glycolysis in epidermolysis bullosa\u2010associated aggressive cutaneous squamous cell carcinoma"],"prefix":"10.1111","volume":"38","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3159-0720","authenticated-orcid":false,"given":"T.","family":"Welponer","sequence":"first","affiliation":[{"name":"Department of Dermatology and Allergology University Hospital of the Paracelsus Medical University  Salzburg Austria"},{"name":"EB House Austria, Research Program for Molecular Therapy of Genodermatoses, Department of Dermatology and Allergology University Hospital of the Paracelsus Medical University  Salzburg Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D. 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K.","family":"Felder","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine University Hospital of the Paracelsus Medical University  Salzburg Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D.","family":"Strunk","sequence":"additional","affiliation":[{"name":"Cell Therapy Institute, Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI\u2010TReCS) Paracelsus Medical University  Salzburg Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"U.","family":"Koller","sequence":"additional","affiliation":[{"name":"EB House Austria, Research Program for Molecular Therapy of Genodermatoses, Department of Dermatology and Allergology University Hospital of the Paracelsus Medical University  Salzburg Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. 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