biostudies-literaturevan Leent MMTNational Heart Foundation of AustraliaCourant Forschungszentrum Geobiologie, Georg-August-Universität GöttingenNIBIB NIH HHSNIDA NIH HHSTeikyo University School of MedicineNHLBI NIH HHSZonMwNational Institutes of HealthAmerican Heart AssociationEmissions Reduction AlbertaEuropean Research CouncilDeutsche ForschungsgemeinschaftHorizon 2020 Framework ProgrammeFUNDINGDutch Research Council (NWO)Horizon 2020Hartstichtingeabe1433https://www.ebi.ac.uk/biostudies/studies/S-EPMC8209679biostudies-literatureUnknown13(584)Macrophages play a central role in the pathogenesis of atherosclerosis. The inflammatory properties of these cells are dictated by their metabolism, of which the mechanistic target of rapamycin (mTOR) signaling pathway is a key regulator. Using myeloid cell-specific nanobiologics in apolipoprotein E-deficient (<i>Apoe</i> ^-/-) mice, we found that targeting the mTOR and ribosomal protein S6 kinase-1 (S6K1) signaling pathways rapidly diminished plaque macrophages' inflammatory activity. By investigating transcriptome modifications, we identified <i>Psap</i>, a gene encoding the lysosomal protein prosaposin, as closely related with mTOR signaling. Subsequent in vitro experiments revealed that <i>Psap</i> inhibition suppressed both glycolysis and oxidative phosphorylation. TransplanScience translational medicineProsaposin mediates inflammation in atherosclerosis.PMC820967919PRE34380423R01 DA049547ZonMW Vici 9181862291713324R01 HL144072ZonMW Vidi 91713324R01 EB00963891818622R35 HL139598CRC 1123-A5research and innovation program (No 667837)consolidator grant 6814937553202018T093P01 HL131478ZonMW Veni 016156059681493R01 HL084312Spinoza grantJTC2018, project MEMORY; 2018T093R01 HL118440CVON2012-03JTC2018CVON2018-270161560592018T028HHSN268201000045CHHSN368201000045C667837R01 HL125703SMIS 103587Sanchez-Gaytan BLPerez-Medina Cvan Leent MMTYe YXKluza EFayad ZAFisher EAJoosten LABNauta SAPasterkamp GKlein EDMulder WJMZhang BNetea MGLameijer MALutgens ERother NNahrendorf MToner YCBekkering SMalkus JTeunissen AJPFay FWojtkiewicz GZhou Xvan der Meel RBeldman TJLi YSwirski FKDuivenvoorden RRiksen NPBoltjes AfalseProsaposin mediates inflammation in atherosclerosis.Macrophages play a central role in the pathogenesis of atherosclerosis. The inflammatory properties of these cells are dictated by their metabolism, of which the mechanistic target of rapamycin (mTOR) signaling pathway is a key regulator. Using myeloid cell-specific nanobiologics in apolipoprotein E-deficient (<i>Apoe</i> ^-/-) mice, we found that targeting the mTOR and ribosomal protein S6 kinase-1 (S6K1) signaling pathways rapidly diminished plaque macrophages' inflammatory activity. By investigating transcriptome modifications, we identified <i>Psap</i>, a gene encoding the lysosomal protein prosaposin, as closely related with mTOR signaling. Subsequent in vitro experiments revealed that <i>Psap</i> inhibition suppressed both glycolysis and oxidative phosphorylation. Transplan2021-01-01T00:00:00Z2021 Mar2026-05-31T05:00:14.158Z2026-04-08T08:10:03.901ZS-EPMC82096793369213010.1126/scitranslmed.abe1433