{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T00:57:16Z","timestamp":1791853036620,"version":"4.3.4"},"reference-count":62,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2025,12,26]],"date-time":"2025-12-26T00:00:00Z","timestamp":1766707200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,12,26]],"date-time":"2025-12-26T00:00:00Z","timestamp":1766707200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82370624"],"award-info":[{"award-number":["82370624"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82403337"],"award-info":[{"award-number":["82403337"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82403596"],"award-info":[{"award-number":["82403596"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Clinical &amp;amp; Translational Med"],"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Lenvatinib resistance (LR) represents a significant obstacle in hepatocellular carcinoma (HCC) treatment. Aldo\u2010keto reductase family 1 member B10 (AKR1B10) is involved in tumour metabolic reprogramming; however, its role in LR remains unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Bioinformatics analyses of public databases were integrated and validated in established LR HCC cell lines. Functional assays (CCK\u20108, flow cytometry and Seahorse XF analysis) were performed to assess proliferation, apoptosis and aerobic glycolysis. Post\u2010translational modifications of AKR1B10 were characterized using co\u2010immunoprecipitation, mass spectrometry and western blot.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>AKR1B10 was identified as a critical driver of resistance by establishing a metabolic positive feedback loop. Bioinformatics analyses and experimental validation demonstrated that AKR1B10 upregulation correlates with therapeutic resistance. Functional studies indicated that AKR1B10 promotes resistance by enhancing aerobic glycolysis. Mechanistically, alanyl\u2010tRNA synthetase 1 mediates lactylation modification at AKR1B10 lysine 173 (K173), stabilizing AKR1B10 by blocking ubiquitin (Ub)\u2010proteasomal degradation. Stabilized AKR1B10 interacts physically with lactate dehydrogenase A (LDHA), promoting LDHA phosphorylation at Y10 and accelerating glycolytic lactate production. The increased lactate subsequently induces histone H3K18 lactylation (H3K18la), which transcriptionally upregulates LDHA expression. Thus, a self\u2010reinforcing AKR1B10\u2013lactate\u2013LDHA amplification circuit is formed. Clinical analyses confirmed elevated AKR1B10 expression in LR HCC patient tissues. Importantly, targeting this axis with the AKR1B10 inhibitor epalrestat (EPA) synergized with lenvatinib, overcoming resistance in xenograft mouse models and patient\u2010derived xenograft models.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>These findings establish AKR1B10 as both a biomarker and a therapeutic target in HCC. They reveal a novel lactylation\u2010driven glycolytic adaptation mechanism and support the clinical translation of combined EPA\u2013lenvatinib therapy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key points<\/jats:title>\n                    <jats:p>\n                      <jats:list list-type=\"bullet\">\n                        <jats:list-item>\n                          <jats:p>AKR1B10 confers lenvatinib resistance by enhancing aerobic glycolysis in HCC cells.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>AKR1B10 undergoes AARS1\u2010mediated lactylation at K173, stabilizing it by antagonizing ubiquitin\u2010proteasomal degradation.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>AKR1B10 promotes LDHA Y10 phosphorylation, boosting lactate production, which drives H3K18la\u2010mediated transcriptional upregulation of LDHA, creating a feed\u2010forward loop.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Targeting AKR1B10 with epalrestat synergizes with lenvatinib to overcome resistance in preclinical models.<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ctm2.70561","type":"journal-article","created":{"date-parts":[[2025,12,27]],"date-time":"2025-12-27T05:56:45Z","timestamp":1766815005000},"source":"Crossref","is-referenced-by-count":15,"title":["AARS1\u2010mediated AKR1B10 lactylation stabilizes an aerobic glycolysis\u2010positive feedback loop to drive lenvatinib resistance in hepatocellular carcinoma"],"prefix":"10.1002","volume":"16","author":[{"given":"Zijian","family":"Liu","sequence":"first","affiliation":[{"name":"Laboratory of Cancer Therapy and Immunity Department of Radiation Oncology and Department of Head and Neck Oncology Cancer Center West China Hospital Sichuan University  Chengdu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingsheng","family":"Yuan","sequence":"additional","affiliation":[{"name":"Department of Liver Transplantation Center &amp; Institute of Organ Transplantation West China Hospital Sichuan University  Chengdu China"},{"name":"Key Laboratory of Transplant Engineering and Immunology NHC West China Hospital Sichuan University  Chengdu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shitong","family":"Su","sequence":"additional","affiliation":[{"name":"Department of Pathology West China Second University Hospital Sichuan University  Chengdu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaqi","family":"Han","sequence":"additional","affiliation":[{"name":"Laboratory of Cancer Therapy and Immunity Department of Radiation Oncology and Department of Head and Neck Oncology Cancer Center West China Hospital Sichuan University  Chengdu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ni","family":"Zeng","sequence":"additional","affiliation":[{"name":"Laboratory of Cancer Therapy and Immunity Department of Radiation Oncology and Department of Head and Neck Oncology Cancer Center West China Hospital Sichuan University  Chengdu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuhan","family":"Ma","sequence":"additional","affiliation":[{"name":"Laboratory of Cancer Therapy and Immunity Department of Radiation Oncology and Department of Head and Neck Oncology Cancer Center West China Hospital Sichuan University  Chengdu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nianyong","family":"Chen","sequence":"additional","affiliation":[{"name":"Laboratory of Cancer Therapy and Immunity Department of Radiation Oncology and Department of Head and Neck Oncology Cancer Center West China Hospital Sichuan University  Chengdu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao","family":"Lv","sequence":"additional","affiliation":[{"name":"Department of Liver Transplantation Center &amp; Institute of Organ Transplantation West China Hospital Sichuan University  Chengdu China"},{"name":"Key Laboratory of Transplant Engineering and Immunology NHC West China Hospital Sichuan University  Chengdu China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,12,26]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21834"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41571\u2010023\u201000825\u20103"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21660"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41571\u2010024\u201000868\u20100"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140\u20106736(18)30207\u20101"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586\u2010021\u201003741\u20107"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.22933"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/mc.22477"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078\u20100432.CCR\u201014\u20102072"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.30519"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1042\/BJ20111322"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.273.19.11429"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms15046556"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2009.11.005"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078\u20100432.CCR\u201004\u20101238"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.27618"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/modpathol.2011.191"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M707650200"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M109.022897"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1002\/mc.22844"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12967\u2010023\u201004403\u20100"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.7150\/ijbs.52927"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2025.217472"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202401399"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2023.11.022"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586\u2010024\u201007620\u20109"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13578\u2010025\u201001415\u20109"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202309290"},{"key":"e_1_2_11_30_1","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.adg4993"},{"key":"e_1_2_11_31_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41419\u2010024\u201006450\u2010x"},{"key":"e_1_2_11_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2019.08.052"},{"key":"e_1_2_11_33_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008\u20105472.CAN\u201020\u20103175"},{"key":"e_1_2_11_34_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13059\u2010021\u201002308\u2010z"},{"key":"e_1_2_11_35_1","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2022.944537"},{"key":"e_1_2_11_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2024.167481"},{"key":"e_1_2_11_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2025.116887"},{"key":"e_1_2_11_38_1","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202414141"},{"key":"e_1_2_11_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2022.215921"},{"key":"e_1_2_11_40_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2018.08.006"},{"key":"e_1_2_11_41_1","doi-asserted-by":"publisher","DOI":"10.1080\/03602530802431439"},{"key":"e_1_2_11_42_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010023\u201035795\u20108"},{"key":"e_1_2_11_43_1","doi-asserted-by":"publisher","DOI":"10.1007\/s13238\u2010021\u201000846\u20107"},{"key":"e_1_2_11_44_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2314128121"},{"key":"e_1_2_11_45_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI174587"},{"key":"e_1_2_11_46_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586\u2010024\u201007992\u2010y"},{"key":"e_1_2_11_47_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.202308099"},{"key":"e_1_2_11_48_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep09520"},{"key":"e_1_2_11_49_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcancer.2022.07.004"},{"key":"e_1_2_11_50_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI69741"},{"key":"e_1_2_11_51_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.06120\u201011"},{"key":"e_1_2_11_52_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejphar.2022.175191"},{"key":"e_1_2_11_53_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41418\u2010024\u201001436\u2010w"},{"key":"e_1_2_11_54_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijbiomac.2022.10.014"},{"key":"e_1_2_11_55_1","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202415530"},{"key":"e_1_2_11_56_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12032\u2010015\u20100633\u20108"},{"key":"e_1_2_11_57_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.271.51.32529"},{"key":"e_1_2_11_58_1","doi-asserted-by":"publisher","DOI":"10.1042\/bj3040391"},{"key":"e_1_2_11_59_1","doi-asserted-by":"publisher","DOI":"10.1016\/0303\u20107207(94)03459\u20107"},{"key":"e_1_2_11_60_1","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2017.6"},{"key":"e_1_2_11_61_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms15308"},{"key":"e_1_2_11_62_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12943\u2010024\u201002008\u20109"},{"key":"e_1_2_11_63_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2013.02.005"}],"container-title":["Clinical and Translational Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ctm2.70561","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/ctm2.70561","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ctm2.70561","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,16]],"date-time":"2026-05-16T11:36:22Z","timestamp":1778931382000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/ctm2.70561"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,26]]},"references-count":62,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2026,1]]}},"alternative-id":["10.1002\/ctm2.70561"],"URL":"https:\/\/doi.org\/10.1002\/ctm2.70561","archive":["Portico"],"relation":{},"ISSN":["2001-1326","2001-1326"],"issn-type":[{"value":"2001-1326","type":"print"},{"value":"2001-1326","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,26]]},"article-number":"e70561"}}