Genital Lichen Sclerosus: From Hidden Mechanisms to Healing Horizons.

Lichen sclerosus (LS) is a chronic inflammatory dermatosis that primarily affects the genital mucosa in both sexes. Although most prevalent in women and characterized by distinct age peaks, its clinical presentation, marked by ivory-white atrophic patches and plaques, often overlaps with other conditions. Delayed diagnosis, frequently due to asymptomatic progression, poses a significant risk of malignant transformation. The etiology of LS is multifactorial, involving a complex interplay of genetic, epigenetic, environmental, and autoimmune factors. Pathogenetically, the disease is characterized by several co-occurring features, including an immune imbalance with elevated pro-inflammatory cytokines, impaired T-regulatory (Treg) cell activity, a persistent local inflammatory state, and dysregulated collagen metabolism with associated fibrosis and scarring. Furthermore, the production of autoantibodies against extracellular matrix protein 1 (ECM1) disrupts skin integrity, while the generation of reactive oxygen species (ROS) further exacerbates tissue damage, autoimmunity, and tumorigenesis. Despite its severe impact on patient quality of life, current diagnostic and therapeutic strategies remain limited. While potent topical corticosteroids represent the gold standard first-line treatment-with topical calcineurin inhibitors serving as a second-line alternative-the lack of a fully elucidated etiopathogenesis continues to restrict curative options. However, recent translational research is paving the way for innovative regenerative therapies. This review provides an updated comprehensive overview of the latest advancements in LS pathogenesis and explores emerging therapeutic landscapes.