{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T18:18:16Z","timestamp":1788286696680,"version":"build-2803163510"},"reference-count":30,"publisher":"National Academy of Sciences","issue":"36","license":[{"start":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T00:00:00Z","timestamp":1788220800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001674","name":"Fondation Leducq","doi-asserted-by":"publisher","award":["19CVD04"],"award-info":[{"award-number":["19CVD04"]}],"id":[{"id":"10.13039\/501100001674","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2026,9,8]]},"abstract":"<jats:p>\n                    Aster proteins (Aster-A, -B, and -C) are crucial for transporting cholesterol from the plasma membrane (PM) to the endoplasmic reticulum (ER). Asters are expressed in a cell type\u2013specific manner across tissues. Their global disruption leads to varied physiological outcomes given the diverse roles of cholesterol throughout the body. We previously identified sterol analogs, such AI-3d, that inhibit all three Aster proteins. However, their utility is limited by toxicity and off-target effects. Here, we report the development of nonsteroidal Aster inhibitors that are active in cells and in vivo, using binding-guided design to generate compounds with isoform-selective affinities. We found that YKJ-124 is a low-toxicity, Aster-A\u2013preferring inhibitor that elevates PM-accessible cholesterol in primary T cells and potentiates store-operated Ca\n                    <jats:sup>2+<\/jats:sup>\n                    entry in Th17 cells, phenocopying Aster-A deficiency. YKJ-300 and YKJ-305 selectively target Aster-C; cocrystal structures and point mutation studies reveal a Ser477-dependent hydrogen bond (Gly in Aster-A\/B) that underlies this specificity. We also explored the in vivo consequences of pharmacologic Aster-C inhibition. YKJ-305 treatment of mice blunted fasting-induced hepatic cholesterol transport and cholesterol ester formation, accompanied by compensatory activation of the SREBP2 pathway. Last, we also identify broader-spectrum inhibitors (YKJ-86) and dual Aster-A\/C inhibitors (YKJ-262) that drive PM cholesterol accumulation in fibroblasts and human intestinal enteroids. Together, these chemical probes enable isoform-resolved manipulation of Aster-dependent cholesterol trafficking and provide a foundation for developing Aster-targeted therapies for cholesterol dysregulation.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2617638123","type":"journal-article","created":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T17:58:11Z","timestamp":1788285491000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":0,"title":["Design and structural basis of selective nonsteroidal inhibitors of aster cholesterol trafficking"],"prefix":"10.1073","volume":"123","author":[{"given":"Hyunsoo","family":"Kim","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/046rm7j60","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Chemistry, University of California","place":["Los Angeles"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3061-6696","authenticated-orcid":false,"given":"Beatriz","family":"Romartinez-Alonso","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04h699437","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Molecular and Cell Biology, Institute of Structural and Chemical Biology, University of Leicester","place":["Leicester, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xu","family":"Xiao","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/046rm7j60","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Pathology and Laboratory Medicine, University of California","place":["Los Angeles"]},{"id":[{"id":"https:\/\/ror.org\/046rm7j60","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Biological Chemistry, University of California","place":["Los Angeles"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8836-4452","authenticated-orcid":false,"given":"Yajing","family":"Gao","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/046rm7j60","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Pathology and Laboratory Medicine, University of California","place":["Los Angeles"]},{"id":[{"id":"https:\/\/ror.org\/046rm7j60","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Biological Chemistry, University of California","place":["Los Angeles"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4399-3976","authenticated-orcid":false,"given":"John Paul","family":"Kennelly","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/046rm7j60","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Pathology and Laboratory Medicine, University of California","place":["Los Angeles"]},{"id":[{"id":"https:\/\/ror.org\/046rm7j60","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Biological Chemistry, University of California","place":["Los Angeles"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandra","family":"Ferrari","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/046rm7j60","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Pathology and Laboratory Medicine, University of California","place":["Los Angeles"]},{"id":[{"id":"https:\/\/ror.org\/046rm7j60","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Biological Chemistry, University of California","place":["Los Angeles"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Li","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/046rm7j60","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Pathology and Laboratory Medicine, University of California","place":["Los Angeles"]},{"id":[{"id":"https:\/\/ror.org\/046rm7j60","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Biological Chemistry, University of California","place":["Los Angeles"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6186-1558","authenticated-orcid":false,"given":"Liujuan","family":"Cui","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/046rm7j60","id-type":"ROR","asserted-by":"publisher"}],"name":"Hematology and Oncology, Department of Medicine, University of California","place":["Los Angeles"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily","family":"Whang","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/046rm7j60","id-type":"ROR","asserted-by":"publisher"}],"name":"Division of Pediatric Gastroenterology, Hepatology and Nutrition, University of California","place":["Los Angeles"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2865-4383","authenticated-orcid":false,"given":"John W. R.","family":"Schwabe","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04h699437","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Molecular and Cell Biology, Institute of Structural and Chemical Biology, University of Leicester","place":["Leicester, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael E.","family":"Jung","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/046rm7j60","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Chemistry, University of California","place":["Los Angeles"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1259-0477","authenticated-orcid":false,"given":"Peter","family":"Tontonoz","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/046rm7j60","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Pathology and Laboratory Medicine, University of California","place":["Los Angeles"]},{"id":[{"id":"https:\/\/ror.org\/046rm7j60","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Biological Chemistry, University of California","place":["Los Angeles"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2026,9,1]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.02882"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1194\/jlr.ILR120000836"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2018.08.033"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.00255-20"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/s42255-022-00722-6"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.adf0966"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI173002"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.adt4169"},{"key":"e_1_3_4_9_2","doi-asserted-by":"crossref","unstructured":"J. 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No To Shinkei 56, 1047\u20131053 (2004).","journal-title":"No To Shinkei"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M410302200"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.25466"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/bs.mie.2021.01.011"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2528400123"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmc.2024.117673"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1107\/S0907444913015308"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1107\/S0907444913000061"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1107\/S0907444910045749"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1701640114"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.1107\/S0907444910007493"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.1107\/S0907444913000565"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1107\/S0907444911001314"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.1107\/S2059798319011471"},{"key":"e_1_3_4_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2020.05.003"},{"key":"e_1_3_4_28_2","doi-asserted-by":"publisher","DOI":"10.1021\/jasms.1c00203"},{"key":"e_1_3_4_29_2","unstructured":"B. Romartinez-Alonso Structure of mouse AsterC bound to YKJ-300. RCSB PDB. https:\/\/www.rcsb.org\/structure\/30JR. Deposited 29 April 2026."},{"key":"e_1_3_4_30_2","unstructured":"B. Romartinez-Alonso Structure of mouse AsterC bound to YKJ-305. RCSB PDB. https:\/\/www.rcsb.org\/structure\/30JI. Deposited 29 April 2026."}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2617638123","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T17:58:39Z","timestamp":1788285519000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/10.1073\/pnas.2617638123"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,1]]},"references-count":30,"journal-issue":{"issue":"36","published-print":{"date-parts":[[2026,9,8]]}},"alternative-id":["10.1073\/pnas.2617638123"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2617638123","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,1]]},"assertion":[{"value":"2026-05-18","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-07-24","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-01","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2617638123"}}