Figure . FGF2 unconventional secretion mechanism. FGF2 secretion follows a unique mechanism involving direct translocation across the plasma membrane. Initially, soluble FGF2 monomers interact directly with the inner leaflet of the plasma membrane via binding to the Na, K-ATPase. Subsequently, FGF2 is transferred to PI(4,5)P 2 within cholesterol-enriched nanodomains, forming FGF2 oligomers. During this process, disulfide-linked FGF2 dimers, mediated by C95, act as intermediates and further self-assemble into tetramer ring structures. The PI(4,5)P 2 -binding site in FGF2 also binds an additional four to five PI(4,5)P 2 molecules through weaker interactions, leading to localized clustering of PI(4,5)P 2 molecules under the FGF2 tetramer. Since PI(4,5)P 2 is a non-bilayer lipid, this clustering is thought to compromise the plasma membrane's integrity, facilitating the formation of a toroidal lipidic pore. Finally, the oligomers are captured and disassembled into dimers at the cell surface through interaction with heparan sulfate proteoglycan glypican-1, resulting in the translocation of FGF2 to the cell exterior.