Fig. 4

Phospholipids mediate signaling in immune cells. a Antigens, costimulatory signals, cytokines, and other factors activate PI3K, which phosphorylates the metabolite PIP2 to phosphatidylinositol-3,4,5-trisphosphate (PIP3). Conversely, PTEN acts in the opposite direction, terminating the PI3K signaling pathway. PIP3 recruits phosphoinositide-dependent kinase-1 (PDK1), activating AKT via phosphorylation at Thr308. In addition, mTORC2 phosphorylates AKT at Ser473. Activated AKT dissociates from the cell membrane to phosphorylate target proteins, such as BAD, FOXO, ACLY, MDM2, and IKK, influencing lipid metabolism, survival, apoptosis, differentiation, and other cellular responses in immune cells. PIP2 activates PLC, producing DAG and IP3. IP3 releases Ca²⁺ ions from the endoplasmic reticulum, leading to the progressive activation of CaM and CaN. CaN hydrolyzes and dephosphorylates NFAT, ultimately promoting its entry into the nucleus to mediate immune cell proliferation and differentiation. DGK converts DAG to PA and, together with PKC, initiates downstream signaling cascades that promote NF-κB entry into the nucleus, modulating the immune response. b Externally transported S1P binds to S1PRs via autocrine or paracrine signaling, regulating pathways such as the PI3K/AKT and MAPK pathways. Created in BioRender