Work

A Mechanistic Map of the Phenotypic Complexity in Recessive Dystrophic Epidermolysis Bullosa Provides Basis for Therapeutic Target Discovery and Drug Repurposing

Year: 2026

Type: article

Abstract: 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's 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.

Source: International Journal of Molecular Sciences

DOI: 10.3390/ijms27198436