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Polyunsaturated fatty acid (PUFA) supplementation is recommended in preterm infants to lower the risk of ROP, however, with no significant improvement in visual acuity. Reasonably, this could be as a result of the non\u2010consideration of PUFA metabolizing enzymes. We hypothesize that abnormal metabolism of the arachidonic acid (AA) pathway may contribute to severe stages of ROP. The present study investigated the AA\u2010metabolizing enzymes in ROP pathogenesis by a targeted gene expression analysis of blood (severe ROP\u2009=\u200970, No\/Mild\u2009=\u200956), placenta (preterm placenta\u2009=\u20096, full term placenta\u2009=\u20093), and human primary retinal cell cultures and further confirmed at the protein level by performing IHC in sections of ROP retina. The lipid metabolites were identified by LC\u2013MS in the vitreous humor (VH; severe ROP\u2009=\u200915, control\u2009=\u200915). Prostaglandins D2 (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.02), leukotrienes B5 (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.0001), 11,12\u2010epoxyeicosatrienoic acid (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.01), and lipid\u2010metabolizing enzymes of the AA pathway such as\n                    <jats:italic>CYP1B1<\/jats:italic>\n                    ,\n                    <jats:italic>CYP2C8<\/jats:italic>\n                    ,\n                    <jats:italic>COX2<\/jats:italic>\n                    , and\n                    <jats:italic>ALOX15<\/jats:italic>\n                    were significantly upregulated while\n                    <jats:italic>EPHX2<\/jats:italic>\n                    was significantly (0.04) downregulated in ROP cases. Genes involved in hypoxic stress, angiogenesis, and apoptosis showed increased expression in ROP. An increase in the metabolic intermediates generated from the AA metabolism pathway further confirmed the role of these enzymes in ROP, while metabolites for\n                    <jats:italic>EPHX2<\/jats:italic>\n                    activity were low in abundance. Inflammatory lipid intermediates were higher compared to anti\u2010inflammatory lipids in VH and showed an association with enzyme activity. Both the placenta of preterm infants who developed ROP and hypoxic retinal cultures showed a reduced expression of\n                    <jats:italic>EPHX2<\/jats:italic>\n                    . These findings suggested a strong involvement of\n                    <jats:italic>EPHX2<\/jats:italic>\n                    in regulating retinal neovascularization and inflammation. The study results underscore the role of arachidonic acid metabolism in the development of ROP and as a potential target for preventing vision loss among preterm\u2010born infants.\n                    <jats:boxed-text content-type=\"graphic\" position=\"anchor\">\n                      <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc16190-fig-0008-m.png\">\n                        <jats:alt-text>image<\/jats:alt-text>\n                      <\/jats:graphic>\n                    <\/jats:boxed-text>\n                  <\/jats:p>","DOI":"10.1111\/jnc.16190","type":"journal-article","created":{"date-parts":[[2024,7,29]],"date-time":"2024-07-29T03:34:28Z","timestamp":1722224068000},"page":"3171-3187","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Arachidonic acid metabolism regulates the development of retinopathy of prematurity among preterm infants"],"prefix":"10.1111","volume":"168","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6929-0830","authenticated-orcid":false,"given":"Saurabh","family":"Kumar","sequence":"first","affiliation":[{"name":"Brien Holden Eye Research Centre LV Prasad Eye Institute  Hyderabad India"},{"name":"Manipal Academy of Higher Education  Manipal India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satish","family":"Patnaik","sequence":"additional","affiliation":[{"name":"Brien Holden Eye Research Centre LV Prasad Eye Institute  Hyderabad India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manjunath B.","family":"Joshi","sequence":"additional","affiliation":[{"name":"Department of Ageing Research, Manipal School of Life Sciences, Manipal Academy of Higher Education  Manipal India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neha","family":"Sharma","sequence":"additional","affiliation":[{"name":"Brien Holden Eye Research Centre LV Prasad Eye Institute  Hyderabad India"},{"name":"Manipal Academy of Higher Education  Manipal India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tarandeep","family":"Kaur","sequence":"additional","affiliation":[{"name":"Brien Holden Eye Research Centre LV Prasad Eye Institute  Hyderabad India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Subhadra","family":"Jalali","sequence":"additional","affiliation":[{"name":"Smt. Kannuri Santhamma Centre for Vitreo Retinal Diseases LV Prasad Eye Institute  Hyderabad India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ramesh","family":"Kekunnaya","sequence":"additional","affiliation":[{"name":"Jasti V Ramanamma Children's Eye Care Centre LV Prasad Eye Institute  Hyderabad India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5064-6921","authenticated-orcid":false,"given":"Aatish","family":"Mahajan","sequence":"additional","affiliation":[{"name":"Brien Holden Eye Research Centre LV Prasad Eye Institute  Hyderabad India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3717-4963","authenticated-orcid":false,"given":"Subhabrata","family":"Chakrabarti","sequence":"additional","affiliation":[{"name":"Brien Holden Eye Research Centre LV Prasad Eye Institute  Hyderabad India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3660-5039","authenticated-orcid":false,"given":"Inderjeet","family":"Kaur","sequence":"additional","affiliation":[{"name":"Brien Holden Eye Research Centre LV Prasad Eye Institute  Hyderabad India"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,7,29]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010022\u201028365\u2010x"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/pr.2013.205"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.2005.03099.x"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10456\u2010007\u20109066\u20100"},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood\u20102007\u201011\u2010126680"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.1021\/acschemneuro.2c00807"},{"key":"e_1_2_12_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/s42255\u2010018\u20100011\u2010x"},{"key":"e_1_2_12_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2014.08.032"},{"key":"e_1_2_12_10_1","doi-asserted-by":"publisher","DOI":"10.1101\/pdb.prot4986"},{"key":"e_1_2_12_11_1","doi-asserted-by":"publisher","DOI":"10.3390\/nu14071333"},{"key":"e_1_2_12_12_1","doi-asserted-by":"publisher","DOI":"10.14670\/HH\u201027.151"},{"key":"e_1_2_12_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2005.09.010"},{"key":"e_1_2_12_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.gene.2013.05.008"},{"key":"e_1_2_12_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/bmb.21552"},{"key":"e_1_2_12_16_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/11.21.2615"},{"key":"e_1_2_12_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ophtha.2014.07.050"},{"key":"e_1_2_12_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaapos.2012.12.155"},{"key":"e_1_2_12_19_1","doi-asserted-by":"publisher","DOI":"10.4161\/cam.1.3.4978"},{"key":"e_1_2_12_20_1","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvr267"},{"key":"e_1_2_12_21_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI123835"},{"key":"e_1_2_12_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature25013"},{"key":"e_1_2_12_23_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20131494"},{"key":"e_1_2_12_24_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-981-16-4247-0_9"},{"key":"e_1_2_12_25_1","doi-asserted-by":"crossref","unstructured":"Kaur T. 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