Exploring TGFBR3 in disease pathogenesis: Mechanisms, clinical implications, and pharmacological modulation

Transforming growth factor beta (TGF-β) receptor 3 (TGFBR3), or betaglycan, is a transmembrane proteoglycan that serves as a coreceptor for TGF-β ligands, modulating TGF-β signaling in a context-dependent manner. Its extracellular domain can undergo proteolytic cleavage, yielding a 120 kDa soluble isoform (soluble transforming growth factor beta receptor 3 (sTGFBR3)) that antagonizes TGF-β signaling by sequestering ligands. Through this dual role, TGFBR3 exerts profound influence over various physiological and pathological processes, including cell survival, stemness, differentiation, cancer metastasis, chemoresistance, and fibrosis, underscoring its significance as both a biomarker and therapeutic target. Despite its significance, regulatory mechanisms, particularly tissue-specific expression, cross-talk with other pathways and post-translational modifications, remain poorly defined. A current thorough review of the prognostic and therapeutic implications of TGFBR3 is still lacking. In this review, we systematically examine the structural features of TGFBR3, and their functional relevance, providing an in-depth analysis of its dysregulation and molecular roles in diseases such as cancer, nervous system disorders, cardiovascular diseases (CVDs), diabetes and infectious diseases. Current experimental approaches are critically evaluated, and gaps in existing literature are highlighted to identify priorities for future research. By synthesizing emerging insights, this review aims to inform the development of TGFBR3-targeted therapies and support the design of innovative clinical and preclinical strategies.