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The cluster of differentiation-36 (CD36) and lectin-like oxLDL receptor-1 (LOX-1) scavenger receptors mediate macrophage uptake of oxidized low-density lipoprotein (oxLDL), which contributes to mitochondrial dysfunction by sustained production of mitochondrial reactive oxygen species (mtROS), as well as membrane depolarization. In the present study, the antioxidant mechanisms of action of the selective synthetic azapeptide CD36 ligand MPE-298 have been revealed. After binding to CD36, MPE-298 was rapidly internalized by and simultaneously induced CD36 endocytosis through activation of the Lyn and Syk (spleen) tyrosine kinases. Within this internalized complex, MPE-298 inhibited oxLDL\/LOX-1-induced chemokine ligand 2 (CCL2) secretion, abolished the production of mtROS, and prevented mitochondrial membrane potential depolarization in macrophages. This occurred through the inhibition of the multiple-component enzyme nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (NOX2) by oxLDL-activated LOX-1, which was further supported by the reduced recruitment of the p47phox subunit and small GTPase (Rac) 1\/2\/3 into the plasma membrane. A new mechanism for alleviating oxLDL-induced oxidative stress and inflammation in macrophages is highlighted using the CD36 ligand MPE-298.<\/jats:p>","DOI":"10.3390\/cells14050385","type":"journal-article","created":{"date-parts":[[2025,3,6]],"date-time":"2025-03-06T06:02:13Z","timestamp":1741240933000},"page":"385","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Selective Azapeptide CD36 Ligand MPE-298 Regulates oxLDL-LOX-1-Mediated Inflammation and Mitochondrial Oxidative Stress in Macrophages"],"prefix":"10.3390","volume":"14","author":[{"given":"Mukandila","family":"Mulumba","sequence":"first","affiliation":[{"name":"Facult\u00e9 de Pharmacie, Universit\u00e9 de Montr\u00e9al, Montr\u00e9al, QC H3C 3J7, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine","family":"Le","sequence":"additional","affiliation":[{"name":"Facult\u00e9 de Pharmacie, Universit\u00e9 de Montr\u00e9al, Montr\u00e9al, QC H3C 3J7, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emmanuelle","family":"Schelsohn","sequence":"additional","affiliation":[{"name":"Institut des Sciences Pharmaceutiques de Suisse Occidentale (ISPSO), Section Sciences Pharmaceutiques, D\u00e9partement des Sciences, Universit\u00e9 de Gen\u00e8ve, 1205 Gen\u00e8ve, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3085-2066","authenticated-orcid":false,"given":"Yoon","family":"Namkung","sequence":"additional","affiliation":[{"name":"Department of Medicine, McGill University, Montreal, QC H4A 3J1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0633-543X","authenticated-orcid":false,"given":"St\u00e9phane A.","family":"Laporte","sequence":"additional","affiliation":[{"name":"Department of Medicine, McGill University, Montreal, QC H4A 3J1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7142-8440","authenticated-orcid":false,"given":"Maria","family":"Febbraio","sequence":"additional","affiliation":[{"name":"Department of Dentistry, University of Alberta, Edmonton, AB T6G 2H5, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2014-4127","authenticated-orcid":false,"given":"Marc J.","family":"Servant","sequence":"additional","affiliation":[{"name":"Facult\u00e9 de Pharmacie, Universit\u00e9 de Montr\u00e9al, Montr\u00e9al, QC H3C 3J7, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sylvain","family":"Chemtob","sequence":"additional","affiliation":[{"name":"Facult\u00e9 de M\u00e9decine, Centre Hospitalier Universitaire Sainte-Justine, Montr\u00e9al, QC H3T 1C5, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3080-2712","authenticated-orcid":false,"given":"William D.","family":"Lubell","sequence":"additional","affiliation":[{"name":"D\u00e9partement de Chimie, Universit\u00e9 de Montr\u00e9al, Montr\u00e9al, QC H3C 3J7, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9392-1989","authenticated-orcid":false,"given":"Sylvie","family":"Marleau","sequence":"additional","affiliation":[{"name":"Facult\u00e9 de Pharmacie, Universit\u00e9 de Montr\u00e9al, Montr\u00e9al, QC H3C 3J7, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8459-2645","authenticated-orcid":false,"given":"Huy","family":"Ong","sequence":"additional","affiliation":[{"name":"Facult\u00e9 de Pharmacie, Universit\u00e9 de Montr\u00e9al, Montr\u00e9al, QC H3C 3J7, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,3,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"ra91","DOI":"10.1126\/scisignal.aaa9623","article-title":"Oxidized LDL-bound CD36 recruits an Na(+)\/K(+)-ATPase-Lyn complex in macrophages that promotes atherosclerosis","volume":"8","author":"Chen","year":"2015","journal-title":"Sci. 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