Thbs4, or thrombospondin 4, is an extracellular matrix protein. It is involved in multiple biological processes such as cell attachment, extracellular matrix protein production, and angiogenesis through the TGFβ signaling pathway [6]. It also mediates important pathways like FAK/PI3K/AKT, which are crucial for cell growth, migration, and survival [1,2,4,5]. Understanding Thbs4's function is essential as it has implications in various physiological and pathological conditions. Genetic models, especially KO/CKO mouse models, can greatly aid in studying its function in vivo.

In multiple cancer types, Thbs4 has been shown to act as an oncogene. In hepatocellular carcinoma (HCC), its overexpression promotes cell proliferation and metastasis, regulating epithelial-mesenchymal transition (EMT) and interacting with integrinβ1 (ITGB1) via the FAK/PI3K/AKT pathway [1]. In gastric cancer, it stimulates cell proliferation, migration, and invasion, potentially through targeting KLF9 [2]. In prostate cancer, overexpression of Thbs4 promotes cancer stem cell-like properties by activating the PI3K/Akt pathway, while its silencing has the opposite effect [4]. In colorectal cancer, increased TGFβ and PDGF-D lead to over-secretion of THBS4 via the PDGFRβ signal, promoting tumor development [6]. In the context of Helicobacter pylori-induced gastric cancer, BM-MSCs-mediated upregulation of Thbs4 promotes angiogenesis through the THBS4/integrin α2 axis, activating the PI3K/AKT pathway in endothelial cells [5]. In keratinocytes, THBS4 stimulates proliferation, migration, and regulates pathways related to inflammation and differentiation [3]. In Duchenne muscular dystrophy mouse models, Thbs4 is associated with fibrosis in skeletal muscles [7]. In the heart, a fibroblast subpopulation named Fibroblast-Thbs4 emerges after tissue stress induction to promote fibrosis [8].

In conclusion, Thbs4 plays a significant role in cancer development, wound healing, muscle fibrosis, and cardiac fibrosis. Studies using gene-knockout or conditional-knockout mouse models could potentially further clarify its role in these disease areas, providing valuable insights into the underlying molecular mechanisms and potentially leading to new therapeutic strategies.