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Expression of the E4 variant of apolipoprotein E (\n                  <jats:italic>APOE<\/jats:italic>\n                  ) greatly increases individuals\u2019 risk of developing AD. In response to lipogenesis in astrocytes, APOE can escape secretion and traffic to the cytoplasmic surface of lipid droplets (LDs), but protein interactors of APOE at the LD were unknown. Here we find that LD-localized APOE physically interacts with the inflammatory lipid signaling enzyme cyclooxygenase-2 (COX-2). Like APOE, COX-2 can avoid the secretory pathway and traffic to LDs in response to lipogenesis. APOE3, but not APOE4, increases COX-2 localization to LDs. Computational modeling, microscopy-based assays, and targeted lipidomics reveal that APOE3 promotes while APOE4 suppresses COX-2 enzymatic activity at LDs and intracellular prostaglandin production. This work identifies a novel and targetable protein-protein interaction of APOE and provides a mechanistic link between\n                  <jats:italic>APOE4<\/jats:italic>\n                  and dysregulated inflammatory lipid signaling.\n                <\/jats:p>","DOI":"10.64898\/2026.06.09.730852","type":"posted-content","created":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T10:35:19Z","timestamp":1781087719000},"source":"Crossref","is-referenced-by-count":0,"title":["APOE interacts with COX-2 on lipid droplets to modulate inflammatory lipid signaling"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0732-3780","authenticated-orcid":false,"given":"Alex E.","family":"Powers","sequence":"first","affiliation":[{"name":"Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-6763-1076","authenticated-orcid":false,"given":"Kajal","family":"Kamble","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-4938-0140","authenticated-orcid":false,"given":"Malvika G.","family":"Nair","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4486-6602","authenticated-orcid":false,"given":"Ian A.","family":"Windham","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA"},{"name":"Laboratory of Structural Biophysics and Mechanobiology, The Rockefeller University, New York, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1124-4217","authenticated-orcid":false,"given":"Gregory E.","family":"Miner","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-9669-3853","authenticated-orcid":false,"given":"Courtney E.","family":"Prim","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0372-4154","authenticated-orcid":false,"given":"C. Allie","family":"Mills","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3004-0148","authenticated-orcid":false,"given":"Scott P.","family":"Lyons","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura E.","family":"Herring","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1416-0438","authenticated-orcid":false,"given":"Venkat R.","family":"Chirasani","sequence":"additional","affiliation":[{"name":"R.L. 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