Interactions between small leucine‐rich proteoglycans and proteases: implications for tissue homeostasis and pathology

Small leucine-rich proteoglycans (SLRPs) are essential regulators of extracellular matrix (ECM) organization and cell signaling. Beyond their structural roles, SLRPs modulate protease activity or serve as their substrates, thereby influencing key physiological processes such as collagen fibrillogenesis, wound healing, skeletal development, and immune surveillance. On the other hand, the dysregulation of SLRP-protease interactions, in pathologies such as fibrosis, chronic inflammation, and cancer, results in aberrant ECM remodeling, immune activation, and altered cell behavior. Here, we review emerging insights into the functional crosstalk between SLRPs and proteases in health and disease. We highlight how these interactions impact tissue integrity and disease progression and explore their potential as diagnostic markers and therapeutic targets in fibrosis, cancer, and inflammatory disorders.