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We aimed to enhance the expression of endogenous HDL components, apolipoprotein A1 (APOA1) and antioxidant enzyme paraoxonase 1 (PON1), and to investigate their athero-protective effects. The CRISPR\/dCas9 technology was used to activate the transcription of endogenous\n                    <jats:italic>APOA1\/PON1<\/jats:italic>\n                    in human hepatocytes (Huh7 line) and\n                    <jats:italic>Apoa1<\/jats:italic>\n                    \/\n                    <jats:italic>Pon1<\/jats:italic>\n                    in apoE\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    mice. The expression of\n                    <jats:italic>APOA1\/PON1<\/jats:italic>\n                    genes was successfully upregulated in hepatocytes, and their proteins were secreted in the culture medium in the presence\/absence of tumor necrosis factor-\u03b1 (TNF\u03b1). APOA1-rich Huh7-derived conditioned medium exerted antioxidant and anti-inflammatory effects in TNF\u03b1-activated EA.hy926 endothelial cells. A single dose of the CRISPR\/dCas9 plasmids i.v. injected in apoE\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    mice increased the expression of hepatic\n                    <jats:italic>Apoa1\/Pon1<\/jats:italic>\n                    and their serum levels up to four weeks. FPLC analysis showed that increased serum APOA1 was distributed between HDL, LDL, and in lipid-free form. These mice also exhibited high levels of hepatic, gallbladder and feces cholesterol, in part due to the upregulation of hepatic scavenger receptor class-B1, cholesterol 7-alpha-hydroxylase, and ATP-binding cassette sub-family-G-member-8 transporter. In apoE\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    mice with upregulated\n                    <jats:italic>Apoa1\/Pon1<\/jats:italic>\n                    , no increased inflammatory stress or innate immune activation were detected, while lipid peroxides were decreased in PON1 mice. Of major interest, the area of aortic lipid deposits was halved in the treated mice. Our findings demonstrate the successful upregulation of endogenous\n                    <jats:italic>Apoa1\/Pon1<\/jats:italic>\n                    in apoE\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    mice by using the CRISPR\/dCas9 system, and highlight new mechanisms for APO1\/PON1 anti-atherosclerotic action, explaining the reduction of aortic lipid deposits.\n                  <\/jats:p>","DOI":"10.1186\/s43556-026-00580-8","type":"journal-article","created":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T23:02:22Z","timestamp":1789686142000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["CRISPR\/dCas9-induced upregulation of endogenous apolipoprotein A1 and paraoxonase 1 genes reduces the aortic lipid deposits in apoE\u2212\/\u2212 mice"],"prefix":"10.1186","volume":"7","author":[{"given":"Laura","family":"Toma","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teodora","family":"Barb\u0103lat\u0103","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica Isabela C\u0103t\u0103lina","family":"H\u0103r\u0103t\u0103u","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriela Maria","family":"Sanda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena Valeria","family":"Fuior","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ioana M\u0103d\u0103lina","family":"Fenyo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Loredan \u015etefan","family":"Niculescu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura-Maria","family":"D\u0103ian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shlomo","family":"Sasson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anca Volumnia","family":"Sima","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2988-9961","authenticated-orcid":false,"given":"Camelia Sorina","family":"Stancu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,9,18]]},"reference":[{"key":"580_CR1","doi-asserted-by":"publisher","unstructured":"Naderi-Meshkin H, Setyaningsih WAW. 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