Thrombospondin 4 (THBS4; TSP4), a crucial component of the extracellular matrix (ECM), serves as an important regulator of tissue homeostasis and pathophysiological processes. As a member of the evolutionarily conserved thrombospondin family, THBS4 is a multidomain adhesive glycoprotein characterized by six distinct structural domains that mediate its diverse biological functions. Through dynamic interactions with various ECM components, THBS4 plays pivotal roles in cellular adhesion, proliferation, inflammatory regulation, and tissue remodeling, establishing it as a key modulator of microenvironmental organization. The transcription and translation of THBS4 gene, the activity of THBS4 protein are tightly regulated by multiple signaling pathways and extracellular cues. Positive regulators of THBS4 include transforming growth factor-β (TGF-β), interferon-γ (IFNγ), granulocyte-macrophage colony-stimulating factor (GM-CSF), bone morphogenetic proteins (BMP12/13), and other other regulatory factors (such as B4GALNT1, ITGA2/ITGB1, PDGFRβ, etc.), which upregulate THBS4 at mRNA and/or protein level. Conversely, oxidized low-density lipoprotein (OXLDL) serves as a potent negative regulator of THBS4. This intricate regulatory network ensures precise spatial and temporal control of THBS4 expression in response to various physiological and pathological stimuli. Functionally, THBS4 acts as a critical signaling node that influences multiple downstream pathways central to cellular behavior and tissue homeostasis. The most well-characterized pathways include: (1) the PI3K/AKT/mTOR axis, which THBS4 modulates through direct and indirect interactions with integrins and growth factor receptors; (2) Wnt/β-catenin signaling, where THBS4 serves as both an activator and inhibitor depending on cellular context; and (3) while suppressing DBET/TRIM69. These diverse signaling connections position THBS4 as a master regulator of cellular responses to microenvironmental changes. Substantial evidence links THBS4 abnormalities to various pathological conditions, including neoplastic diseases, cardiovascular disorders, fibrotic conditions, neurodegenerative diseases, musculoskeletal disorders, and atopic dermatitis. In cancer biology, THBS4 demonstrates context-dependent roles, functioning as either a tumor suppressor or promoter depending on the tumor type and microenvironment. In cardiovascular systems, THBS4 participates in both adaptive remodeling and maladaptive fibrosis processes. THBS4 involvement in fibrotic diseases stems from its ability to modulate ECM deposition and turnover. The diagnostic and therapeutic potential of THBS4 is particularly promising in oncology and cardiovascular medicine. As a biomarker, THBS4 expression patterns show significant correlations with disease progression and patient outcomes. Therapeutically, targeting THBS4-mediated pathways offers novel opportunities for developing precision medicine approaches, including anti-fibrotic strategies, tumor microenvironment modulation, and tissue repair promotion. This comprehensive review systematically examines three key aspects of THBS4 research: (1) The fundamental biological functions of THBS4 in ECM organization; (2) The mechanistic involvement of THBS4 in various disease pathogenesis; (3) The emerging potential of THBS4 as both diagnostic biomarker and therapeutic target. By integrating recent advances from molecular studies, animal models, and clinical investigations, this review provides a framework for understanding THBS4's multifaceted roles in health and disease. The synthesis of current knowledge highlights critical research gaps and future directions for exploring THBS4-targeted interventions across multiple disease contexts. With its unique position at the inters ection of ECM biology and cellular signaling, THBS4 represents a promising frontier for developing novel diagnostic tools and therapeutic strategies in precision medicine.