Tspan4, a member of the tetraspanin family, is a key regulator of migrasome formation and is recognized as a marker protein for migrasomes [1,2,3,4,5,6,7]. Migrasomes are extracellular vesicles related to cell migration, involved in releasing signaling molecules, expelling damaged mitochondria, and facilitating intercellular communication [5]. Tspan4 is also reported to interact with the histamine H4 receptor, though it doesn't affect H4R-mediated G protein signaling [8].

In various diseases, Tspan4 has shown significant impacts. In proliferative vitreoretinopathy (PVR), TGF-β1 increases Tspan4 expression in retinal pigmented epithelium (RPE) cells, leading to migrasome production which promotes RPE activation and PVR development. Inhibiting Tspan4 in RPE cells reduces the ability to initiate experimental PVR [1]. In glioblastoma (GBM), Tspan4 promotes GBM progression by interacting with epidermal growth factor receptor (EGFR) and regulating its stability. Knockdown of Tspan4 inhibits GBM cell proliferation, invasion in vitro, and tumorigenicity in vivo [2]. Tspan4 expression is also associated with atherosclerosis progression, pan-cancer (especially GBM), and is upregulated in foam cells from patients with atherosclerosis, correlating with poor prognosis [3].

In conclusion, Tspan4 is crucial for migrasome-related functions and plays significant roles in diseases such as PVR, GBM, and atherosclerosis. The study of Tspan4 using gene-knockout or conditional-knockout models in mice, as well as other loss-of-function experiments, has provided insights into its functions in these disease conditions, potentially paving the way for new therapeutic strategies targeting Tspan4.