APOL2 is an endoplasmic reticulum-localized lipid-binding protein with emerging roles in multiple physiological and pathological processes. The protein contains a non-classical four-helix bundle motif in its N-terminal domain structurally related to other apolipoprotein L family members 1. While initially characterized as a BH3-motif-containing protein, APOL2 does not function as a classical BH3-only pro-death protein and does not regulate apoptosis or autophagy 2. Recent evidence reveals distinct functions: (1) In liver fibrosis, TGF-β1 stimulation induces APOL2 in hepatic stellate cells, where it binds SERCA2 to trigger ER stress and activate the PERK-HES1 axis, promoting fibrosis progression 3. (2) In gut immunity, APOL2 (human equivalent of mouse APOL9a/b) specifically coats Bacteroidales bacteria through ceramide-1-phosphate interactions, inducing outer membrane vesicle production that enhances intestinal immune responses 4. (3) In gastric cancer, APOL2 stabilizes Ku80 protein via enhanced deubiquitylation, promoting NHEJ-mediated DNA repair and conferring radioresistance, with high expression correlating to poor prognosis 5. Circulating APOL2 levels are reduced in APOL1 risk allele carriers, suggesting complex regulation within the apolipoprotein L family 6. APOL2 expression is additionally implicated in cholesterol metabolism and cancer stem cell drug resistance pathways 7.