XKR4 is a phospholipid scramblase that mediates phosphatidylserine (PtdSer) externalization on apoptotic cell surfaces 1. During apoptosis, caspase-mediated cleavage of XKR4 activates the protein, which then undergoes dimerization and is further activated by the nuclear protein fragment XRCC4 2. Mechanistically, XKR4 adopts a novel membrane-embedded conformation with negatively charged acidic residues that induces membrane thinning, facilitating lipid scrambling 3. PtdSer exposure serves as an "eat me" signal recognized by macrophages for efficient clearance of dying cells; defective XKR4-mediated scrambling impairs this process and promotes inflammation 1. Unlike ubiquitously expressed XKR8, XKR4 demonstrates tissue-specific expression patterns 1. Clinically, XKR4 polymorphisms show associations with taxane-induced peripheral neuropathy susceptibility in breast cancer patients 4, and have modest associations with bipolar disorder clinical characteristics 5. Additionally, XKR4 variants correlate with prolactin concentrations in cattle exposed to fescue toxicosis 6, suggesting broader roles in neuroendocrine regulation. XKR4 represents a conserved mechanism for clearing apoptotic cells, essential for maintaining tissue homeostasis and preventing inflammatory complications.