CLEC3A: overview of an extracellular matrix lectin linking cartilage biology, tumor progression, and host defense

C-type lectin domain family 3 member A (CLEC3A) is an extracellular matrix (ECM)-associated protein involved in cartilage biology, cell signaling, and innate host defense. Over more than two decades of research at the Institute for Clinical Chemistry, University of Cologne, we have shown that CLEC3A, originally identified in cartilage, is a multifunctional regulator of tissue homeostasis and disease processes. Structurally, it belongs to the tetranectin subgroup of C-type lectins and contains domains that enable ECM association and multimer formation. Beyond its structural role in cartilage, CLEC3A modulates tissue-type plasminogen activator-mediated plasmin generation and contributes to extracellular matrix remodeling and cell-matrix interactions affecting adhesion and signaling. Altered CLEC3A expression has been reported in degenerative diseases such as osteoarthritis and intervertebral disc degeneration, as well as in cancer, where it is linked to PI3K–AKT signaling, tumor progression, and immune regulation, including programmed cell death-ligand 1 (PD-L1) regulation. CLEC3A serves as a precursor for bioactive antimicrobial peptides generated by proteolytic cleavage, which show activity against a broad range of bacterial and fungal pathogens, including multidrug-resistant organisms and Candida auris, mainly via membrane-disruptive mechanisms. Full-length CLEC3A also exhibits intrinsic antimicrobial activity. In vivo studies in biomaterial-associated infection models show reduced bacterial burden and inflammation, and peptide modifications can enhance potency, stability, and cytocompatibility. These findings highlight CLEC3A as a promising candidate for translational research in degenerative disease, oncology, and infection, although the underlying receptor-mediated mechanisms remain to be fully elucidated.