{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T08:43:03Z","timestamp":1777624983876,"version":"3.51.4"},"reference-count":110,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"47","funder":[{"DOI":"10.13039\/100004339","name":"Sanofi","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004339","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Adv."],"published-print":{"date-parts":[[2025,11,21]]},"abstract":"<jats:p>Sickle cell disease (SCD), an inherited blood disorder caused by mutation of the \u03b2-globin gene, results in sickle-shaped erythrocytes, organ damage, and increased mortality. Current therapeutic options are limited, and innovative treatments to induce fetal hemoglobin (HbF) are needed. Adenosine monophosphate\u2013activated protein kinase (AMPK) comprises a family of 12 isoforms. In the present study, single-cell RNA sequencing of bone marrow cells revealed that AMPK\u03b21 isoform (AMPK\u03b11\u03b21\u03b31) predominates in the erythroid lineage. AMPK\u03b21 activators increased the expression of HbF in erythroid cells from SCD donors and decreased sickling in vitro through activation of nuclear factor erythroid 2\u2013related factor 2 (NRF2) but independently from direct Kelch-like ECH-associated protein 1 (KEAP1) inhibition, by way of a noncanonical NRF2 pathway, as shown by phosphorylation of Unc-51\u2013like autophagy-activating kinase 1 (ULK1) and sequestosome 1\/p62 (SQSTM1). In vivo studies in Townes SCD mice treated with the selective AMPK\u03b21 activator PF-06409577 confirmed increased HbF in circulating erythrocytes, associated with decreased reactive oxygen species and reduced chronic inflammation markers. Collectively, these findings establish selective AMPK\u03b21 activation as a promising therapeutic approach to induce HbF in hemoglobinopathies.<\/jats:p>","DOI":"10.1126\/sciadv.adx1144","type":"journal-article","created":{"date-parts":[[2025,11,19]],"date-time":"2025-11-19T18:58:54Z","timestamp":1763578734000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":1,"title":["Selective AMPK\u03b21 activation induces fetal hemoglobin in human erythroid cells and sickle cell mice via the noncanonical NRF2 pathway"],"prefix":"10.1126","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2084-971X","authenticated-orcid":true,"given":"Yannis","family":"Hara","sequence":"first","affiliation":[{"name":"Immunology and Inflammation, Sanofi, Cambridge, MA, USA."},{"name":"Rare Blood Disorders, Sanofi, Waltham, MA, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-8141-6628","authenticated-orcid":true,"given":"Viktor T.","family":"Lemgart","sequence":"additional","affiliation":[{"name":"Genomic Medicine Unit, Sanofi, Cambridge, MA, USA."},{"name":"Oncology, Sanofi, Cambridge, MA, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Samuel","family":"Lessard","sequence":"additional","affiliation":[{"name":"Rare Blood Disorders, Sanofi, Waltham, MA, USA."},{"name":"Target, Disease and Systems Biology, Sanofi, Cambridge, MA, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0678-9853","authenticated-orcid":true,"given":"Courtney J.","family":"Mercadante","sequence":"additional","affiliation":[{"name":"Immunology and Inflammation, Sanofi, Cambridge, MA, USA."},{"name":"Rare Blood Disorders, Sanofi, Waltham, MA, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4549-4783","authenticated-orcid":true,"given":"Jean-Antoine","family":"Ribeil","sequence":"additional","affiliation":[{"name":"Section of Hematology and Medical Oncology, Boston University Aram V. Chobanian &amp; Edward Avedisian School of Medicine, Boston Medical Center, Center of Excellence in Sickle Cell Disease, Boston, MA, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexandra","family":"Hicks","sequence":"additional","affiliation":[{"name":"Immunology and Inflammation, Sanofi, Cambridge, MA, USA."},{"name":"Rare Blood Disorders, Sanofi, Waltham, MA, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pauline","family":"Rimmele","sequence":"additional","affiliation":[{"name":"Rare Blood Disorders, Sanofi, Waltham, MA, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2967-6974","authenticated-orcid":true,"given":"David R.","family":"Light","sequence":"additional","affiliation":[{"name":"Rare Blood Disorders, Sanofi, Waltham, MA, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"221","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2020007645"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2022.10233"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrdp.2018.10"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1177\/1535370219900494"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1510865"},{"key":"e_1_3_2_7_2","first-page":"3091","article-title":"Macrophage metabolic rewiring improves heme-suppressed efferocytosis and tissue damage in sickle cell disease","volume":"141","author":"Sharma R.","year":"2023","unstructured":"R. Sharma, A. Antypiuk, S. Z. Vance, D. Manwani, Q. Pearce, J. E. Cox, X. An, K. Yazdanbakhsh, F. Vinchi, Macrophage metabolic rewiring improves heme-suppressed efferocytosis and tissue damage in sickle cell disease. Blood 141, 3091\u20133108 (2023).","journal-title":"Blood"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI133639"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.3390\/ijerph18041832"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(17)36918-1"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2020.265462"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2309676"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2309673"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2031054"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2117175"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1609677"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1038\/d41587-023-00016-6"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2023021220"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1002\/ajh.27635"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdx219"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1002\/ajh.26956"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199505183322001"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.278.5339.873"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.exphem.2022.07.005"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2018.213462"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2023022190"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2023023399"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-022-05312-w"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-021-00904-0"},{"key":"e_1_3_2_30_2","first-page":"2756","article-title":"Molecular basis of polycomb group protein-mediated fetal hemoglobin repression","volume":"141","author":"Qin K.","year":"2023","unstructured":"K. Qin, X. Lan, P. Huang, M. S. Saari, E. Khandros, C. A. Keller, B. Giardine, O. Abdulmalik, J. Shi, R. C. Hardison, G. A. Blobel, Molecular basis of polycomb group protein-mediated fetal hemoglobin repression. Blood 141, 2756\u20132770 (2023).","journal-title":"Blood"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.adk6129"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.adn8750"},{"key":"e_1_3_2_33_2","doi-asserted-by":"publisher","DOI":"10.3390\/antiox12030740"},{"key":"e_1_3_2_34_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41580-022-00547-x"},{"key":"e_1_3_2_35_2","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.116.237925"},{"key":"e_1_3_2_36_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2018.04.009"},{"key":"e_1_3_2_37_2","doi-asserted-by":"publisher","DOI":"10.1002\/hep4.1799"},{"key":"e_1_3_2_38_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2018.01.008"},{"key":"e_1_3_2_39_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2017-11-814335"},{"key":"e_1_3_2_40_2","doi-asserted-by":"publisher","DOI":"10.1002\/ajh.25313"},{"key":"e_1_3_2_41_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2019-131313"},{"key":"e_1_3_2_42_2","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2019000838"},{"key":"e_1_3_2_43_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2010-10-314096"},{"key":"e_1_3_2_44_2","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.96409"},{"key":"e_1_3_2_45_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.exphem.2018.09.004"},{"key":"e_1_3_2_46_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2018.02.001"},{"key":"e_1_3_2_47_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncb2152"},{"key":"e_1_3_2_48_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M705325200"},{"key":"e_1_3_2_49_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2018.06.013"},{"key":"e_1_3_2_50_2","doi-asserted-by":"publisher","DOI":"10.1080\/15548627.2020.1712108"},{"key":"e_1_3_2_51_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1196371"},{"key":"e_1_3_2_52_2","doi-asserted-by":"publisher","DOI":"10.15252\/embj.2022113349"},{"key":"e_1_3_2_53_2","doi-asserted-by":"publisher","DOI":"10.1111\/febs.12905"},{"key":"e_1_3_2_54_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms12030"},{"key":"e_1_3_2_55_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.6b00866"},{"key":"e_1_3_2_56_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.exphem.2017.02.003"},{"key":"e_1_3_2_57_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2015-08-663245"},{"key":"e_1_3_2_58_2","doi-asserted-by":"publisher","DOI":"10.1039\/c6ib00105j"},{"key":"e_1_3_2_59_2","doi-asserted-by":"publisher","DOI":"10.1002\/jha2.712"},{"key":"e_1_3_2_60_2","doi-asserted-by":"publisher","DOI":"10.3390\/cells11071200"},{"key":"e_1_3_2_61_2","doi-asserted-by":"publisher","DOI":"10.1038\/emm.2016.16"},{"key":"e_1_3_2_62_2","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2018.191403"},{"key":"e_1_3_2_63_2","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2022009444"},{"key":"e_1_3_2_64_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M110.102467"},{"key":"e_1_3_2_65_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.exphem.2016.09.006"},{"key":"e_1_3_2_66_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13287-024-04014-6"},{"key":"e_1_3_2_67_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ygcen.2022.114009"},{"key":"e_1_3_2_68_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.xcrm.2021.100474"},{"key":"e_1_3_2_69_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1509158112"},{"key":"e_1_3_2_70_2","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2018017574"},{"key":"e_1_3_2_71_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2019-129479"},{"key":"e_1_3_2_72_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2017-10-810531"},{"key":"e_1_3_2_73_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1306033"},{"key":"e_1_3_2_74_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2018.01.049"},{"key":"e_1_3_2_75_2","doi-asserted-by":"publisher","DOI":"10.1089\/ars.2015.6571"},{"key":"e_1_3_2_76_2","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.81090"},{"key":"e_1_3_2_77_2","first-page":"382","article-title":"Nrf2 sensitizes ferroptosis through l-2-hydroxyglutarate-mediated chromatin modifications in sickle cell disease","volume":"142","author":"Xi C.","year":"2023","unstructured":"C. Xi, J. Pang, W. Zhi, C. S. Chang, U. Siddaramappa, H. Shi, A. Horuzsko, B. S. Pace, X. Zhu, Nrf2 sensitizes ferroptosis through l-2-hydroxyglutarate-mediated chromatin modifications in sickle cell disease. Blood 142, 382\u2013396 (2023).","journal-title":"Blood"},{"key":"e_1_3_2_78_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1715971"},{"key":"e_1_3_2_79_2","doi-asserted-by":"publisher","DOI":"10.1101\/gad.13.1.76"},{"key":"e_1_3_2_80_2","doi-asserted-by":"publisher","DOI":"10.1177\/1535370219825859"},{"key":"e_1_3_2_81_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M307633200"},{"key":"e_1_3_2_82_2","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2022008710"},{"key":"e_1_3_2_83_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2021-146071"},{"key":"e_1_3_2_84_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1008097"},{"key":"e_1_3_2_85_2","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.abg4544"},{"key":"e_1_3_2_86_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2013.12.014"},{"key":"e_1_3_2_87_2","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.30887"},{"key":"e_1_3_2_88_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2022.113572"},{"key":"e_1_3_2_89_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.22.9.2883-2892.2002"},{"key":"e_1_3_2_90_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.00118-16"},{"key":"e_1_3_2_91_2","doi-asserted-by":"publisher","DOI":"10.1242\/dmm.049463"},{"key":"e_1_3_2_92_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2010-11-319137"},{"key":"e_1_3_2_93_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2023-173922"},{"key":"e_1_3_2_94_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V128.22.1293.1293"},{"key":"e_1_3_2_95_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2021-149536"},{"key":"e_1_3_2_96_2","unstructured":"I. Imara \u201cImara announces results of interim analyses of tovinontrine (IMR-687) phase 2b clinical trials in sickle cell disease and beta-thalassemia \u201d GlobeNewswire 5 April 2022."},{"key":"e_1_3_2_97_2","doi-asserted-by":"publisher","DOI":"10.1111\/cts.12604"},{"key":"e_1_3_2_98_2","doi-asserted-by":"publisher","DOI":"10.30802\/AALAS-CM-17-000124"},{"key":"e_1_3_2_99_2","doi-asserted-by":"publisher","DOI":"10.1111\/bjh.14158"},{"key":"e_1_3_2_100_2","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.89761"},{"key":"e_1_3_2_101_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1611770"},{"key":"e_1_3_2_102_2","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.127860"},{"key":"e_1_3_2_103_2","doi-asserted-by":"publisher","DOI":"10.1177\/20458940211056806"},{"key":"e_1_3_2_104_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.967193"},{"key":"e_1_3_2_105_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.isci.2023.108269"},{"key":"e_1_3_2_106_2","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2021004615"},{"key":"e_1_3_2_107_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.trsl.2022.10.007"},{"key":"e_1_3_2_108_2","doi-asserted-by":"publisher","DOI":"10.1155\/2013\/831596"},{"key":"e_1_3_2_109_2","doi-asserted-by":"publisher","DOI":"10.1111\/bjh.18771"},{"key":"e_1_3_2_110_2","first-page":"196","article-title":"Determination of RBC Survival in C57BL\/6 and C57BL\/6-Tg(UBC-GFP) Mice","volume":"65","author":"Dholakia U.","year":"2015","unstructured":"U. Dholakia, S. Bandyopadhyay, E. A. Hod, K. A. Prestia, Determination of RBC Survival in C57BL\/6 and C57BL\/6-Tg(UBC-GFP) Mice. Comp. Med. 65, 196\u2013201 (2015).","journal-title":"Comp. Med."},{"key":"e_1_3_2_111_2","doi-asserted-by":"publisher","DOI":"10.1038\/nbt1047"}],"container-title":["Science Advances"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.science.org\/doi\/pdf\/10.1126\/sciadv.adx1144","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,24]],"date-time":"2025-11-24T19:43:33Z","timestamp":1764013413000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.science.org\/doi\/10.1126\/sciadv.adx1144"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,21]]},"references-count":110,"journal-issue":{"issue":"47","published-print":{"date-parts":[[2025,11,21]]}},"alternative-id":["10.1126\/sciadv.adx1144"],"URL":"https:\/\/doi.org\/10.1126\/sciadv.adx1144","relation":{},"ISSN":["2375-2548"],"issn-type":[{"value":"2375-2548","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,21]]},"assertion":[{"value":"2025-02-28","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-10-14","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-11-19","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"eadx1144"}}