Cathepsin S: molecular mechanisms in inflammatory and immunological processes

Abstract

Cathepsin S (CTSS), a lysosomal cysteine protease predominantly expressed in immune cells, governs inflammatory and immunological cascades through proteolytic activity. Beyond maintaining lysosomal proteostasis through protein degradation, CTSS executes dual immunomodulatory functions: intracellularly processing antigen-presenting molecules and modulating inflammatory signaling cascades; extracellularly activating protease-activated receptors (PARs) and remodeling the extracellular matrix (ECM). Its dysregulation drives pathology in autoimmune disorders, chronic inflammation, and neoplasia, establishing CTSS as a multifaceted therapeutic target. This review comprehensively explores the contributions of CTSS signaling in immune-mediated inflammatory diseases, critically evaluates its therapeutic potential, highlighting its significance in the development of innovative treatment strategies.

Keywords: cathepsin S (CTSS); immunoregulation; inflammatory disease; molecular mechanism; therapeutic targets.

Figure 1

Stress-induced upregulation of CTSS drives inflammatory disease progression.

Figure 2

CTSS regulation by upstream inflammatory transcriptional factors. CTSS expression is dynamically modulated by inflammatory transcription factors with opposing regulatory effects: IRF-1, PU.1 and TFEB act as transcriptional activators, whereas TGF-β/Smad function as repressors. STAT3 exerts context-dependent effects, influenced by upstream signals (e.g., IL-6/IL-10 pro-/anti-inflammatory cytokines or H₂S).

Figure 3

CTSS-driven inflammatory signal transduction. CTSS acts as a proteolytic hub to amplifies inflammatory responses through modulation of transcriptional activators (e.g., NF-κB activation), exposure of cryptic signaling domains (e.g., PAR2, MHC-II) and release of bioactive inflammatory factors (e.g., FKN/CX3CL1).