Molecular mechanisms of skin fibrosis : Fibrosis can be defined as an excessive and deregulated deposition of extracellular matrix proteins, causing loss of physiological architecture and dysfunction of different tissues and organs. In the skin, fibrosis represents the hallmark of several acquired (e.g. systemic sclerosis and hypertrophic scars) and inherited (i.e. dystrophic epidermolysis bullosa) diseases. A complex series of interactions among a variety of cellular types and a wide range of molecular players drive the fibro genic process, often in a context-dependent manner. However, the pathogenic mechanisms leading to skin fibrosis are not completely elucidated. In this scenario, an increasing body of evidence has recently disclosed the involvement of Notch signalling cascade in fibrosis of the skin and other organs. Despite its apparent simplicity, Notch represents one of the most multifaceted, strictly regulated and intricate pathways with still unknown features both in health and disease conditions. Starting from the most recent advances in Notch activation and regulation, this review focuses on the pro-fibrotic function of Notch pathway in fibro proliferative skin disorders describing molecular networks, interplay with other pro-fibrotic molecules and pathways, including the transforming growth factor-β1, and therapeutic strategies under developments. Notch activation, processing and regulation Notch signalling cascade: from receptor‑ligand binding To transcriptional outcomes : An overview of Notch maturation, activation and processing. Before integration into the plasma membrane, Notch receptor is decorated with different glycan’s by a complex series of enzymatic reactions occurring within the endoplasmic reticulum (ER) or the Golgi network. Post-translational adducts determine a differential responsiveness of Notch-expressing cells to the ligands. Thereafter, Notch receptor is cleaved at the level of the S1 cleavage site (S1) by a furin-like convertase residing in the trans-Golgi network. The cleavage results in the formation of a heterodimeric receptor, consisting of a Notch extracellular domain (NECD) and a Notch transmembrane domain (NTMD) held together by Ca2+-dependent ionic bonds . Similarly, also Notch ligand undergoes a “maturation process” consisting in its endocytosis, ubiquitination by the Neutralized and Mindbomb E3 ubiquitin ligases and “recycling” to the plasma membrane . Notch ligands belong to the Delta/Serrate/LAG2 (DSL) protein family. After ligand binding, the mature Notch receptor is subjected to two successive proteolytic cleavages (S2 and S3 cleavage). The first cleavage is exerted by an ADAM metalloprotease (e.g. ADAM17) close the transmembrane domain to generate the Notch extracellular truncation (NEXT) fragment (S2 cleavage). The second is operated by the γ-secretase complex within the transmembrane domain the NEXT fragment (S3 cleavage) or in endosomes, to dump into the cytoplasm the biologically active Notch intracellular domain (NICD). In the cell nucleus, NICD forms trimeric complex with RBPJ and MAML1, which initiates transcription of Notch downstream target genes. Notch expression and role in skin physiology and pathology : Skin architecture and Notch pathway member distribution. (Left panel) Organization of human skin. The epidermis is the thinnest and most superficial layer of the skin, it is connected to the underlying dermis through the cutaneous basement membrane zone (BMZ), the highly specialized structure which connects the epidermis to the dermis ensuring skin integrity and stability against mechanical insults. Epidermis is arranged into four distinct layers: basal, spinous, granular and stratum conium (or horny layer). The deepest layer of the epidermis, overlaying the BMZ, is the basal layer which is followed by the spinous and the granular layers whilst the stratum conium is the outermost. Each layer is typified by keratinocytes (KCs) at various stages of differentiation. KCs of the basal layer are characterized by their ability to proliferate. Indeed, in the basal layer, epidermal stem cells (SCs) divide to self-renew and produce transient amplifying cells (also known as committed progenitors—CPs), which possess a more limited proliferation capability. In the early phases of differentiation, CPs detach from the BMZ and move toward the stratum corneum becoming terminally differentiated cells (TDs) devoid of nuclei. (Right panel) Expression pattern of Notch receptors (NOTCH1-4) and Notch ligands (JAG1 and DLL1) in human skin. Conclusion : The findings Summarized in this review show that the Notch pathway Pervasively regulates different aspects of skin homeostasis and its dysregulation can underlie the path mechanisms of fibrosis. Thus, targeting the Notch cascade Could represent a relevant tool for future therapeutic Approaches in fibrotic skin disorders.