Cathepsin S: a double-edged protease in barrier damage, neuroimmune inflammation, and tissue repair, with...

Cathepsin S (CTSS) is a lysosomal cysteine protease traditionally recognized for its role in invariant-chain degradation and major histocompatibility complex class II antigen presentation. However, unlike many lysosomal cathepsins, CTSS remains active at neutral or mildly acidic pH, enabling proteolytic functions at the cell surface and within extracellular inflammatory microenvironments. This property makes CTSS particularly relevant to skin biology, where barrier disruption, immune activation, neuroimmune signaling, extracellular matrix remodeling, angiogenesis, fibrosis, tumor progression, and tissue repair often coexist. This review summarizes the context-dependent and double-edged role of CTSS in inflammation and repair, with emphasis on its dermatological relevance. CTSS can promote pathogenic inflammation through multiple mechanisms, including regulation of antigen presentation, activation of cytokine pathways such as IL-36γ, degradation of antimicrobial and barrier-associated proteins, activation of protease-activated receptor 2, cleavage of fractalkine/CX3CL1, and modulation of neuroimmune circuits involved in itch and pain. These mechanisms implicate CTSS in inflammatory and immune-mediated dermatoses such as psoriasis, atopic dermatitis, vitiligo, rosacea, seborrheic dermatitis, and cutaneous lupus-related autoimmunity. CTSS may also contribute to extracellular matrix turnover, fibroblast activation, vascular remodeling, skin aging, keloid formation, systemic sclerosis-associated fibrosis, and cutaneous melanoma progression. Conversely, CTSS is not uniformly pathogenic. In selected contexts, it may support macrophage, M2 polarization, matrix remodeling, wound repair, and inflammatory resolution. This duality suggests that the biological impact of CTSS depends on its timing, location, cellular source, substrate specificity, and disease stage. Recent pharmacological findings, including rebound CTSS activity and increased CTSS protein mass after repeated administration of a selective CTSS inhibitor, further indicate that simple systemic inhibition may be insufficient or potentially counterproductive. Therefore, CTSS should be viewed as a context-dependent protease switch rather than a universally harmful enzyme. A better understanding of its compartment-specific and stage-specific functions may help guide more selective therapeutic strategies, including local delivery, substrate-selective modulation, combination approaches, and disease-stage-adapted intervention. This framework may refine the development of CTSS-targeted therapies for skin diseases and skin-related immune disorders.