{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T17:16:58Z","timestamp":1793121418918,"version":"4.5.0"},"reference-count":50,"publisher":"Elsevier BV","license":[{"start":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T00:00:00Z","timestamp":1790812800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"},{"start":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T00:00:00Z","timestamp":1790812800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/legal\/tdmrep-license"},{"start":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T00:00:00Z","timestamp":1784246400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100020595","name":"National Science and Technology Council","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100020595","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["elsevier.com","sciencedirect.com"],"crossmark-restriction":true},"short-container-title":["European Journal of Pharmaceutical Sciences"],"published-print":{"date-parts":[[2026,10]]},"DOI":"10.1016\/j.ejps.2026.107614","type":"journal-article","created":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T15:04:37Z","timestamp":1784559877000},"page":"107614","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":3,"special_numbering":"C","title":["LARS inhibition overcomes regorafenib resistance in hepatocellular carcinoma via ferroptosis and drug metabolism"],"prefix":"10.1016","volume":"225","author":[{"given":"Tung-Yao","family":"Tsai","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hsuan-Hwai","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi-Chiao","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vijesh Kumar","family":"Yadav","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chun-Chen","family":"Ko","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yih-Giun","family":"Cherng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2928-5401","authenticated-orcid":false,"given":"Shiue-Wei","family":"Lai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"78","reference":[{"issue":"12","key":"10.1016\/j.ejps.2026.107614_bib0005","doi-asserted-by":"crossref","first-page":"1683","DOI":"10.1001\/jamaoncol.2017.3055","article-title":"The burden of primary liver cancer and underlying etiologies from 1990 to 2015 at the global, regional, and national level: results from the global burden of disease study 2015","volume":"3","author":"Akinyemiju","year":"2017","journal-title":"JAMA Oncol."},{"issue":"4","key":"10.1016\/j.ejps.2026.107614_bib0024","first-page":"1069","article-title":"Mechanistic target of rapamycin inhibitors: successes and challenges as cancer therapeutics","volume":"2","author":"Bhaoighill","year":"2019","journal-title":"Cancer Drug Resist. (Alhambra, Calif.)"},{"issue":"3","key":"10.1016\/j.ejps.2026.107614_bib0001","first-page":"229","article-title":"Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"74","author":"Bray","year":"2024","journal-title":"CA Cancer J. Clin."},{"issue":"10064","key":"10.1016\/j.ejps.2026.107614_bib0038","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1016\/S0140-6736(16)32453-9","article-title":"Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial","volume":"389","author":"Bruix","year":"2017","journal-title":"Lancet (Lond., Engl.)"},{"key":"10.1016\/j.ejps.2026.107614_bib0009","article-title":"Tremelimumab plus durvalumab in advanced hepatocellular carcinoma treatment: a pharmacovigilance comparative analysis between eudravigilance and Himalaya study","author":"Castellana","year":"2025","journal-title":"Hosp. Pharm."},{"issue":"8","key":"10.1016\/j.ejps.2026.107614_bib0014","doi-asserted-by":"crossref","first-page":"1041","DOI":"10.4254\/wjh.v7.i8.1041","article-title":"Advanced hepatocellular carcinoma and sorafenib: diagnosis, indications, clinical and radiological follow-up","volume":"7","author":"Colagrande","year":"2015","journal-title":"World J. Hepatol."},{"issue":"4","key":"10.1016\/j.ejps.2026.107614_bib0046","doi-asserted-by":"crossref","first-page":"1493","DOI":"10.1007\/s10753-023-01823-4","article-title":"Atya HB: camptothecin sensitizes hepatocellular carcinoma cells to sorafenib- induced ferroptosis via suppression of Nrf2","volume":"46","author":"Elkateb","year":"2023","journal-title":"Inflammation"},{"issue":"9","key":"10.1016\/j.ejps.2026.107614_bib0018","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s12276-019-0308-1","article-title":"Anti-tumoral activity of single and combined regorafenib treatments in preclinical models of liver and gastrointestinal cancers","volume":"51","author":"Fondevila","year":"2019","journal-title":"Exp Mol Med"},{"key":"10.1016\/j.ejps.2026.107614_bib0022","first-page":"2933","article-title":"A human leucyl-tRNA synthetase as an anticancer target","volume":"8","author":"Gao","year":"2015","journal-title":"OncoTargets Ther."},{"key":"10.1016\/j.ejps.2026.107614_bib0006","first-page":"4317","volume":"38","author":"Gordan","year":"2020"},{"issue":"6","key":"10.1016\/j.ejps.2026.107614_bib0045","doi-asserted-by":"crossref","first-page":"518","DOI":"10.1016\/j.dld.2015.03.010","article-title":"Metronomic capecitabine as second-line treatment in hepatocellular carcinoma after sorafenib failure","volume":"47","author":"Granito","year":"2015","journal-title":"Dig. and Liver Dis."},{"key":"10.1016\/j.ejps.2026.107614_bib0017","article-title":"Experience with regorafenib in the treatment of hepatocellular carcinoma","volume":"14","author":"Granito","year":"2021"},{"issue":"9863","key":"10.1016\/j.ejps.2026.107614_bib0016","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1016\/S0140-6736(12)61900-X","article-title":"Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial","volume":"381","author":"Grothey","year":"2013","journal-title":"Lancet (Lond., Engl.)"},{"key":"10.1016\/j.ejps.2026.107614_bib0034","doi-asserted-by":"crossref","DOI":"10.3389\/fphar.2023.1207496","article-title":"Mechanism of sorafenib resistance associated with ferroptosis in HCC","volume":"14","author":"Guo","year":"2023","journal-title":"Front. Pharmacol."},{"issue":"36","key":"10.1016\/j.ejps.2026.107614_bib0004","doi-asserted-by":"crossref","first-page":"10327","DOI":"10.3748\/wjg.v21.i36.10327","article-title":"Transarterial chemoembolization in hepatocellular carcinoma treatment: Barcelona clinic liver cancer staging system","volume":"21","author":"Han","year":"2015","journal-title":"World J. Gastroenterol."},{"key":"10.1016\/j.ejps.2026.107614_bib0041","doi-asserted-by":"crossref","DOI":"10.3389\/fmed.2024.1464610","article-title":"EGFR bypass activation mediates acquired resistance to regorafenib in hepatocellular carcinoma","volume":"11","author":"Hu","year":"2024","journal-title":"Front. Med."},{"issue":"1","key":"10.1016\/j.ejps.2026.107614_bib0029","first-page":"207","article-title":"Ferroptosis: from basic research to clinical therapeutics in hepatocellular carcinoma","volume":"11","author":"Huang","year":"2023","journal-title":"J. Clin. Transl. Hepatol."},{"issue":"4","key":"10.1016\/j.ejps.2026.107614_bib0019","doi-asserted-by":"crossref","first-page":"2990","DOI":"10.1097\/JS9.0000000000002294","article-title":"Advancements in elucidating the mechanisms of Sorafenib resistance in hepatocellular carcinoma","volume":"111","author":"Huang","year":"2025","journal-title":"Int. J. Surg. (Lond., Engl.)"},{"issue":"4","key":"10.1016\/j.ejps.2026.107614_bib0023","doi-asserted-by":"crossref","DOI":"10.1016\/j.celrep.2021.109031","article-title":"Leucine-sensing mechanism of leucyl-tRNA synthetase 1 for mTORC1 activation","volume":"35","author":"Kim","year":"2021","journal-title":"Cell Rep."},{"issue":"4","key":"10.1016\/j.ejps.2026.107614_bib0020","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1159\/000542285","article-title":"Regorafenib for hepatocellular carcinoma in real-world practice (REFINE): a prospective, observational study","volume":"14","author":"Kim","year":"2025","journal-title":"Liver Cancer"},{"issue":"10","key":"10.1016\/j.ejps.2026.107614_bib0021","article-title":"Randomized phase II study comparing two doses of regorafenib in second-line treatment for advanced hepatocellular carcinoma","volume":"7","author":"Koroki","year":"2025","journal-title":"JHEP Rep."},{"issue":"2","key":"10.1016\/j.ejps.2026.107614_bib0003","doi-asserted-by":"crossref","first-page":"204","DOI":"10.17998\/jlc.2025.07.25","article-title":"Public health strategies for hepatocellular carcinoma: from risk factors to prevention and control","volume":"25","author":"Lee","year":"2025","journal-title":"J. Liver Cancer"},{"key":"10.1016\/j.ejps.2026.107614_bib0042","doi-asserted-by":"crossref","unstructured":"Li L., Wang X., Xu H., Liu X., Xu K.: Perspectives and mechanisms for targeting ferroptosis in the treatment of hepatocellular carcinoma. 2022, 9 2022.","DOI":"10.3389\/fmolb.2022.947208"},{"issue":"9","key":"10.1016\/j.ejps.2026.107614_bib0025","doi-asserted-by":"crossref","first-page":"4946","DOI":"10.1093\/nar\/gkaa189","article-title":"Molecular basis of the multifaceted functions of human leucyl-tRNA synthetase in protein synthesis and beyond","volume":"48","author":"Liu","year":"2020","journal-title":"Nucleic Acids Res."},{"key":"10.1016\/j.ejps.2026.107614_bib0028","doi-asserted-by":"crossref","first-page":"2493","DOI":"10.2147\/JHC.S500084","article-title":"Roles and mechanisms of ferroptosis in sorafenib resistance for hepatocellular carcinoma","volume":"11","author":"Liu","year":"2024","journal-title":"J. Hepatocell. Carcinoma"},{"issue":"1","key":"10.1016\/j.ejps.2026.107614_bib0002","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1038\/s41572-020-00240-3","article-title":"Hepatocellular carcinoma","volume":"7","author":"Llovet","year":"2021","journal-title":"Nat. Rev. Dis. Primers"},{"issue":"7","key":"10.1016\/j.ejps.2026.107614_bib0032","doi-asserted-by":"crossref","first-page":"1732","DOI":"10.1002\/ijc.28159","article-title":"Iron-dependent cell death of hepatocellular carcinoma cells exposed to sorafenib","volume":"133","author":"Louandre","year":"2013","journal-title":"Int. J. Cancer"},{"issue":"3","key":"10.1016\/j.ejps.2026.107614_bib0011","doi-asserted-by":"crossref","first-page":"e484","DOI":"10.1002\/onco.13566","article-title":"FDA supplemental approval summary: lenvatinib for the treatment of unresectable hepatocellular carcinoma","volume":"26","author":"Nair","year":"2021","journal-title":"Oncologist"},{"key":"10.1016\/j.ejps.2026.107614_bib0027","doi-asserted-by":"crossref","unstructured":"Shi Q., Chi Y., Peng Z., Li C., Zhao J., Zhang J.: Identification of amino acid metabolism-related gene Leucyl-tRNA synthetase 1 (LARS1) as a potential prognostic and therapeutic target in hepatocellular carcinoma. 2025, 15 2025.","DOI":"10.3389\/fonc.2025.1675018"},{"issue":"2","key":"10.1016\/j.ejps.2026.107614_bib0026","doi-asserted-by":"crossref","first-page":"229","DOI":"10.3858\/emm.2008.40.2.229","article-title":"Implication of leucyl-tRNA synthetase 1 (LARS1) over-expression in growth and migration of lung cancer cells detected by siRNA targeted knock-down analysis","volume":"40","author":"Shin","year":"2008","journal-title":"Exp. Mol. Med."},{"issue":"13","key":"10.1016\/j.ejps.2026.107614_bib0033","doi-asserted-by":"crossref","first-page":"966","DOI":"10.1089\/ars.2020.8024","article-title":"Nuclear factor erythroid 2-related factor 2 in regulating cancer metabolism","volume":"33","author":"Smolkov\u00e1","year":"2020","journal-title":"Antioxid. Redox Signal."},{"issue":"11","key":"10.1016\/j.ejps.2026.107614_bib0008","doi-asserted-by":"crossref","first-page":"986","DOI":"10.1093\/oncolo\/oyae142","article-title":"Atezolizumab plus bevacizumab as first-line systemic therapy for hepatocellular carcinoma: a multi-institutional cohort study","volume":"29","author":"Storandt","year":"2024","journal-title":"Oncologist"},{"issue":"1","key":"10.1016\/j.ejps.2026.107614_bib0035","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1002\/hep.28251","article-title":"Activation of the p62-Keap1-NRF2 pathway protects against ferroptosis in hepatocellular carcinoma cells","volume":"63","author":"Sun","year":"2016","journal-title":"Hepatology"},{"issue":"5","key":"10.1016\/j.ejps.2026.107614_bib0039","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1111\/cas.12907","article-title":"Multikinase inhibitor regorafenib inhibits the growth and metastasis of colon cancer with abundant stroma","volume":"107","author":"Takigawa","year":"2016","journal-title":"Cancer Sci."},{"issue":"12","key":"10.1016\/j.ejps.2026.107614_bib0013","doi-asserted-by":"crossref","first-page":"5384","DOI":"10.7150\/thno.41616","article-title":"Targeted sequencing reveals the mutational landscape responsible for sorafenib therapy in advanced hepatocellular carcinoma","volume":"10","author":"Tang","year":"2020","journal-title":"Theranostics"},{"issue":"2","key":"10.1016\/j.ejps.2026.107614_bib0044","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1007\/s00432-017-2556-6","article-title":"Metronomic capecitabine as second-line treatment for hepatocellular carcinoma after sorafenib discontinuation","volume":"144","author":"Trevisani","year":"2018","journal-title":"J. Cancer Res. Clin. Oncol."},{"key":"10.1016\/j.ejps.2026.107614_bib0040","first-page":"814","article-title":"Clinical outcomes of sorafenib treatment failure for advanced hepatocellular carcinoma and candidates for regorafenib treatment in real-world practice","volume":"48","author":"Uchikawa","year":"2018"},{"issue":"6","key":"10.1016\/j.ejps.2026.107614_bib0007","doi-asserted-by":"crossref","first-page":"510","DOI":"10.1159\/000533166","article-title":"Atezolizumab in combination with bevacizumab for the management of patients with hepatocellular carcinoma in the first-line setting: systematic literature review and meta-analysis","volume":"12","author":"Vogel","year":"2023","journal-title":"Liver Cancer"},{"key":"10.1016\/j.ejps.2026.107614_bib0010","article-title":"Navigating second-line therapy after immunotherapy in advanced HCC","author":"Vogel","year":"2025","journal-title":"JHEP Rep."},{"issue":"5","key":"10.1016\/j.ejps.2026.107614_bib0036","doi-asserted-by":"crossref","first-page":"2345","DOI":"10.21037\/jgo-21-237","article-title":"Identification and validation of ferroptosis-associated gene-based on immune score as prognosis markers for hepatocellular carcinoma patients","volume":"12","author":"Wang","year":"2021","journal-title":"J. Gastrointest. Oncol."},{"key":"10.1016\/j.ejps.2026.107614_bib0037","doi-asserted-by":"crossref","unstructured":"Wang W., Pan F., Lin X., Yuan J., Tao C., Wang R.: Ferroptosis-related hub genes in hepatocellular carcinoma: prognostic signature, immune-related, and drug resistance analysis. 2022, 13 2022.","DOI":"10.3389\/fgene.2022.907331"},{"key":"10.1016\/j.ejps.2026.107614_bib0030","doi-asserted-by":"crossref","DOI":"10.1016\/j.biopha.2023.116074","article-title":"From synergy to resistance: navigating the complex relationship between sorafenib and ferroptosis in hepatocellular carcinoma","volume":"170","author":"Wang","year":"2024","journal-title":"Biomed. Pharmacother."},{"key":"10.1016\/j.ejps.2026.107614_bib0049","doi-asserted-by":"crossref","unstructured":"Wang Q., Li K., Li L., Li Q., Qi Y., Liu K., Yuan H., Lin P.: The role and therapeutic potential of glucose metabolism in multidrug resistance of cancer. 2025, 13 2025.","DOI":"10.3389\/fcell.2025.1584630"},{"issue":"10","key":"10.1016\/j.ejps.2026.107614_bib0012","doi-asserted-by":"crossref","first-page":"3129","DOI":"10.1158\/1535-7163.MCT-08-0013","article-title":"Preclinical overview of sorafenib, a multikinase inhibitor that targets both Raf and VEGF and PDGF receptor tyrosine kinase signaling","volume":"7","author":"Wilhelm","year":"2008","journal-title":"Mol. Cancer The.r"},{"key":"10.1016\/j.ejps.2026.107614_bib0050","doi-asserted-by":"crossref","unstructured":"Ye Y., Yu B., Wang H., Yi F.: Glutamine metabolic reprogramming in hepatocellular carcinoma. 2023,10 2023.","DOI":"10.3389\/fmolb.2023.1242059"},{"issue":"3","key":"10.1016\/j.ejps.2026.107614_bib0048","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1038\/s41419-024-06584-y","article-title":"Metabolism-regulated ferroptosis in cancer progression and therapy","volume":"15","author":"Ye","year":"2024","journal-title":"Cell Death Dis."},{"key":"10.1016\/j.ejps.2026.107614_bib0043","article-title":"The effect of ferroptosis-related genes on prognosis and tumor mutational burden in hepatocellular carcinoma","author":"Zhang","year":"2021","journal-title":"J. Oncol."},{"issue":"7","key":"10.1016\/j.ejps.2026.107614_bib0031","doi-asserted-by":"crossref","first-page":"698","DOI":"10.1038\/s41419-021-03998-w","article-title":"Sorafenib fails to trigger ferroptosis across a wide range of cancer cell lines","volume":"12","author":"Zheng","year":"2021","journal-title":"Cell Death Dis."},{"issue":"5","key":"10.1016\/j.ejps.2026.107614_bib0015","doi-asserted-by":"crossref","first-page":"614","DOI":"10.1038\/aps.2017.5","article-title":"New knowledge of the mechanisms of sorafenib resistance in liver cancer","volume":"38","author":"Zhu","year":"2017","journal-title":"Acta pharmacol. Sin."},{"issue":"12","key":"10.1016\/j.ejps.2026.107614_bib0047","doi-asserted-by":"crossref","DOI":"10.1083\/jcb.202208103","article-title":"mTORC1 beyond anabolic metabolism: regulation of cell death","volume":"221","author":"Zhu","year":"2022","journal-title":"J. Cell Biol."}],"updated-by":[{"DOI":"10.1016\/j.ejps.2026.107695","type":"erratum","label":"Erratum","source":"publisher","updated":{"date-parts":[[2026,10,25]],"date-time":"2026-10-25T00:00:00Z","timestamp":1792886400000}}],"container-title":["European Journal of Pharmaceutical Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0928098726001880?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0928098726001880?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"}],"deposited":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T02:38:50Z","timestamp":1787107130000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S0928098726001880"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10]]},"references-count":50,"alternative-id":["S0928098726001880"],"URL":"https:\/\/doi.org\/10.1016\/j.ejps.2026.107614","relation":{},"ISSN":["0928-0987"],"issn-type":[{"value":"0928-0987","type":"print"}],"subject":[],"published":{"date-parts":[[2026,10]]},"assertion":[{"value":"Elsevier","name":"publisher","label":"This article is maintained by"},{"value":"LARS inhibition overcomes regorafenib resistance in hepatocellular carcinoma via ferroptosis and drug metabolism","name":"articletitle","label":"Article Title"},{"value":"European Journal of Pharmaceutical Sciences","name":"journaltitle","label":"Journal Title"},{"value":"https:\/\/doi.org\/10.1016\/j.ejps.2026.107614","name":"articlelink","label":"CrossRef DOI link to publisher maintained version"},{"value":"article","name":"content_type","label":"Content Type"},{"value":"\u00a9 2026 The Authors. Published by Elsevier B.V.","name":"copyright","label":"Copyright"}],"article-number":"107614"}}