Extracellular matrix in skin diseases: The road to new therapies

[Display omitted] •ECM-target therapy for skin diseases has been overlooked and many opportunities remain unexplored.•Numerous breakthroughs have been made in EB, but not for other ECM-related genetic skin disorders.•Targeting ECM stiffness seems promising, but countless options await to be explored in skin tumors.•Several questions regarding autoimmune bullous dermatoses pathomechanisms remain unanswered.•Multidisciplinary approaches might help overcome potential constraints of ECM-target therapies. The extracellular matrix (ECM) is a vital structure with a dynamic and complex organization that plays an essential role in tissue homeostasis. In the skin, the ECM is arranged into two types of compartments: interstitial dermal matrix and basement membrane (BM). All evidence in the literature supports the notion that direct dysregulation of the composition, abundance or structure of one of these types of ECM, or indirect modifications in proteins that interact with them is linked to a wide range of human skin pathologies, including hereditary, autoimmune, and neoplastic diseases. Even though the ECM’s key role in these pathologies has been widely documented, its potential as a therapeutic target has been overlooked. This review discusses the molecular mechanisms involved in three groups of skin ECM-related diseases - genetic, autoimmune, and neoplastic – and the recent therapeutic progress and opportunities targeting ECM. This article describes the implications of alterations in ECM components and in BM-associated molecules that are determinant for guaranteeing its function in different skin disorders. Also, ongoing clinical trials on ECM-targeted therapies are discussed together with future opportunities that may open new avenues for treating ECM-associated skin diseases.