{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T05:01:18Z","timestamp":1790226078605,"version":"4.1.0"},"reference-count":87,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T00:00:00Z","timestamp":1790035200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Recessive dystrophic epidermolysis bullosa (RDEB) is a genodermatosis caused by loss-of-function mutations in the COL7A1 gene, producing a complex and heterogeneous phenotype. Clinical manifestations include skin fragility, local and systemic inflammation, impaired wound healing, dysbiosis, pain, and pruritus, increasing the risk of skin cancer. This work aimed to develop an actionable model of RDEB\u2019s molecular mechanisms to identify and prioritize therapeutic targets for drug repurposing. Transcriptomic data of skin biopsies from pediatric RDEB patients and unaffected individuals were used to build the mechanistic map of the disease. This model, combined with machine learning, made it possible to infer actionable targets from the map circuits and identify candidate drugs capable of reversing the transcriptomic alterations. The resulting map is defined by 13 altered signaling circuits and 10 effector proteins which were linked to disease hallmarks including inflammation, fibrosis, and tumor progression. Analysis of the map identified 66 actionable targets with 74 drug candidates. Among them, overrepresentation analysis showed enrichment of phosphodiesterases and antineoplastic and immunomodulating agents. Finally, 16 drugs were prioritized for their potential to revert circuit alterations without potentiating unintended effects, with bendroflumethiazide and ibutilide showing the highest impact. This mechanistic model delivers the first functional disease map of RDEB and reveals promising therapeutic candidates targeted by approved drugs.<\/jats:p>","DOI":"10.3390\/ijms27198436","type":"journal-article","created":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T13:32:12Z","timestamp":1790083932000},"page":"8436","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Mechanistic Map of the Phenotypic Complexity in Recessive Dystrophic Epidermolysis Bullosa Provides Basis for Therapeutic Target Discovery and Drug Repurposing"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0682-5225","authenticated-orcid":false,"given":"Sara","family":"Herr\u00e1iz-Gil","sequence":"first","affiliation":[{"name":"Departamento de Bioingenier\u00eda, Universidad Carlos III de Madrid, ROR Code 03ths8210, Avenida de la Universidad, 30 (Edificio Sabatini), 28911 Legan\u00e9s, 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Rev. Dis. Primers"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"455","DOI":"10.2147\/TCRM.S386923","article-title":"Innovations in the Treatment of Dystrophic Epidermolysis Bullosa (DEB): Current Landscape and Prospects","volume":"19","author":"Hou","year":"2023","journal-title":"Ther. Clin. Risk Manag."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"614","DOI":"10.1111\/bjd.18921","article-title":"Consensus reclassification of inherited epidermolysis bullosa and other disorders with skin fragility","volume":"183","author":"Has","year":"2020","journal-title":"Br. J. Dermatol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"440","DOI":"10.1111\/bjd.18104","article-title":"Chronic tissue damage: A common pathomechanism of genodermatoses","volume":"181","author":"Has","year":"2019","journal-title":"Br. J. Dermatol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1186\/s13023-025-04034-2","article-title":"Tissue and systemic inflammation in dystrophic epidermolysis bullosa: A systematic review and meta-analysis","volume":"20","author":"Karakioulaki","year":"2025","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1573","DOI":"10.1007\/s12094-019-02073-3","article-title":"Epidemiology and natural history of cutaneous squamous cell carcinoma in recessive dystrophic epidermolysis bullosa patients: 20 years\u2019 experience of a reference centre in Spain","volume":"21","author":"Castelo","year":"2019","journal-title":"Clin. Transl. Oncol."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Condorelli, A.G., Dellambra, E., Logli, E., Zambruno, G., and Castiglia, D. (2019). Epidermolysis Bullosa-Associated Squamous Cell Carcinoma: From Pathogenesis to Therapeutic Perspectives. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20225707"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1223","DOI":"10.1111\/ced.14592","article-title":"Evidence for cutaneous dysbiosis in dystrophic epidermolysis bullosa","volume":"46","author":"Bar","year":"2021","journal-title":"Clin. Exp. Dermatol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"774","DOI":"10.1111\/iwj.13922","article-title":"Longitudinal study of wound healing status and bacterial colonisation of Staphylococcus aureus and Corynebacterium diphtheriae in epidermolysis bullosa patients","volume":"20","author":"Fuentes","year":"2023","journal-title":"Int. Wound J."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"664","DOI":"10.1038\/s41467-025-55934-7","article-title":"Systems immunology integrates the complex endotypes of recessive dystrophic epidermolysis bullosa","volume":"16","author":"Hirt","year":"2025","journal-title":"Nat. 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