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This study investigates the role of\n                    <jats:italic>Aff3ir-ORF2<\/jats:italic>\n                    , a novel nested gene variant, in disturbed flow-induced endothelial cell activation and atherosclerosis. We demonstrate that disturbed shear stress significantly reduces\n                    <jats:italic>Aff3ir-ORF2<\/jats:italic>\n                    expression in athero-prone regions. Using three distinct mouse models with manipulated\n                    <jats:italic>Aff3ir-ORF2<\/jats:italic>\n                    expression, we demonstrate that\n                    <jats:italic>Aff3ir-ORF2<\/jats:italic>\n                    exerts potent anti-inflammatory and anti-atherosclerotic effects in\n                    <jats:italic>\n                      Apoe\n                      <jats:sup>-\/-<\/jats:sup>\n                    <\/jats:italic>\n                    mice. RNA sequencing revealed that interferon regulatory factor 5 (\n                    <jats:italic>Irf5<\/jats:italic>\n                    ), a key regulator of inflammatory processes, mediates inflammatory responses associated with\n                    <jats:italic>Aff3ir-ORF2<\/jats:italic>\n                    deficiency.\n                    <jats:italic>Aff3ir-ORF2<\/jats:italic>\n                    interacts with\n                    <jats:italic>Irf5<\/jats:italic>\n                    , promoting its retention in the cytoplasm, thereby inhibiting the\n                    <jats:italic>Irf5<\/jats:italic>\n                    -dependent inflammatory pathways. Notably,\n                    <jats:italic>Irf5<\/jats:italic>\n                    knockdown in\n                    <jats:italic>Aff3ir-ORF2<\/jats:italic>\n                    deficient mice almost completely rescues the aggravated atherosclerotic phenotype. Moreover, endothelial-specific\n                    <jats:italic>Aff3ir-ORF2<\/jats:italic>\n                    supplementation using the CRISPR\/Cas9 system significantly ameliorated endothelial activation and atherosclerosis. These findings elucidate a novel role for\n                    <jats:italic>Aff3ir-ORF2<\/jats:italic>\n                    in mitigating endothelial inflammation and atherosclerosis by acting as an inhibitor of\n                    <jats:italic>Irf5<\/jats:italic>\n                    , highlighting its potential as a valuable therapeutic approach for treating atherosclerosis.\n                  <\/jats:p>","DOI":"10.7554\/elife.103413","type":"journal-article","created":{"date-parts":[[2024,12,13]],"date-time":"2024-12-13T07:25:52Z","timestamp":1734074752000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.103413","source":"Crossref","is-referenced-by-count":1,"title":["Disruption of the novel nested gene Aff3ir mediates disturbed flow-induced atherosclerosis in 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