{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,2]],"date-time":"2026-11-02T20:35:02Z","timestamp":1793651702294,"version":"4.5.1"},"reference-count":52,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,10,15]],"date-time":"2025-10-15T00:00:00Z","timestamp":1760486400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,10,15]],"date-time":"2025-10-15T00:00:00Z","timestamp":1760486400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100001809","name":"the National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["82370608 to Y.G."],"award-info":[{"award-number":["82370608 to Y.G."]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001809","name":"the National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["82470626 to H.X."],"award-info":[{"award-number":["82470626 to H.X."]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"name":"the Department of Education of Anhui Province","award":["2022AH040160 to Y.G."],"award-info":[{"award-number":["2022AH040160 to Y.G."]}]},{"name":"the Department of Education of Anhui Province","award":["2022AH051182 to H.X."],"award-info":[{"award-number":["2022AH051182 to H.X."]}]},{"name":"the National Natural Science Foundation of Anhui Province","award":["2208085MH204 to Y.G."],"award-info":[{"award-number":["2208085MH204 to Y.G."]}]},{"name":"the Research Fund of Anhui Institute of translational medicine","award":["2023zhyx-C55 to H.X."],"award-info":[{"award-number":["2023zhyx-C55 to H.X."]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:p>Sorafenib is the standard treatment for advanced hepatocellular carcinoma (HCC), yet resistance limits its efficacy. The Hedgehog (HH) signaling pathway contributes to drug resistance by maintaining HCC stem cell characteristics, but its role at the single-cell level is underexplored. Utilizing single-cell RNA sequencing (scRNA-seq) and machine learning, we identified solute carrier family 25 member 39 (SLC25A39) as a key regulator of the HH pathway. Analyses of various cohorts revealed that elevated SLC25A39 correlates with poor prognosis in HCC patients. SLC25A39 knockdown inhibited cancer stem cell characteristics and reduced sorafenib resistance in vitro. Furthermore, combined SLC25A39 suppression and sorafenib treatment significantly hindered HCC progression in both in vitro and in vivo models. These findings highlight the potential of shSLC25A39 to enhance sorafenib sensitivity , presenting a new avenue for combating drug resistance and enhancing therapeutic effectiveness.<\/jats:p>","DOI":"10.1038\/s41598-025-20008-7","type":"journal-article","created":{"date-parts":[[2025,10,15]],"date-time":"2025-10-15T11:14:22Z","timestamp":1760526862000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["SLC25A39 regulates Hedgehog signaling to promote tumor progression and sorafenib resistance in hepatocellular carcinoma"],"prefix":"10.1038","volume":"15","author":[{"given":"Qian","family":"Qiu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hehe","family":"Yin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lulu","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiwei","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qianqian","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengqi","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuting","family":"Qian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yatong","family":"Ruan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zihao","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiatao","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Ke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Dai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weijie","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yufeng","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Honghai","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,10,15]]},"reference":[{"key":"20008_CR1","doi-asserted-by":"publisher","first-page":"137","DOI":"10.3892\/ol.2020.12398","volume":"21","author":"S Chen","year":"2021","unstructured":"Chen, S. et al. MicroRNA-200a and microRNA-141 have a synergetic effect on the suppression of epithelial-mesenchymal transition in liver cancer by targeting STAT4. Oncol. Lett. 21, 137. https:\/\/doi.org\/10.3892\/ol.2020.12398 (2021).","journal-title":"Oncol. Lett."},{"key":"20008_CR2","doi-asserted-by":"publisher","first-page":"926","DOI":"10.1097\/hep.0000000000000237","volume":"79","author":"AD Ladd","year":"2024","unstructured":"Ladd, A. D., Duarte, S., Sahin, I. & Zarrinpar, A. Mechanisms of drug resistance in HCC. Hepatology 79, 926\u2013940. https:\/\/doi.org\/10.1097\/hep.0000000000000237 (2024).","journal-title":"Hepatology"},{"key":"20008_CR3","doi-asserted-by":"publisher","first-page":"378","DOI":"10.1056\/NEJMoa0708857","volume":"359","author":"JM Llovet","year":"2008","unstructured":"Llovet, J. M. et al. Sorafenib in advanced hepatocellular carcinoma. N. Engl. J. Med. 359, 378\u2013390. https:\/\/doi.org\/10.1056\/NEJMoa0708857 (2008).","journal-title":"N. Engl. J. Med."},{"key":"20008_CR4","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1016\/j.ctrv.2018.05.006","volume":"68","author":"JL Raoul","year":"2018","unstructured":"Raoul, J. L. et al. Systemic therapy for intermediate and advanced hepatocellular carcinoma: Sorafenib and beyond. Cancer Treat. Rev. 68, 16\u201324. https:\/\/doi.org\/10.1016\/j.ctrv.2018.05.006 (2018).","journal-title":"Cancer Treat. Rev."},{"key":"20008_CR5","doi-asserted-by":"publisher","first-page":"87","DOI":"10.1038\/s41392-020-0187-x","volume":"5","author":"W Tang","year":"2020","unstructured":"Tang, W. et al. The mechanisms of sorafenib resistance in hepatocellular carcinoma: theoretical basis and therapeutic aspects. Signal Transduct. Target. Ther. 5, 87. https:\/\/doi.org\/10.1038\/s41392-020-0187-x (2020).","journal-title":"Signal Transduct. Target. Ther."},{"key":"20008_CR6","doi-asserted-by":"publisher","first-page":"3470","DOI":"10.7150\/thno.92646","volume":"14","author":"Y Zhou","year":"2024","unstructured":"Zhou, Y. et al. GPAT3 is a potential therapeutic target to overcome sorafenib resistance in hepatocellular carcinoma. Theranostics 14, 3470\u20133485. https:\/\/doi.org\/10.7150\/thno.92646 (2024).","journal-title":"Theranostics"},{"key":"20008_CR7","doi-asserted-by":"publisher","first-page":"e103181","DOI":"10.15252\/embj.2019103181","volume":"39","author":"Z Lin","year":"2020","unstructured":"Lin, Z. et al. RNA m(6) A methylation regulates sorafenib resistance in liver cancer through FOXO3- mediated autophagy. EMBO J. 39, e103181. https:\/\/doi.org\/10.15252\/embj.2019103181 (2020).","journal-title":"EMBO J."},{"key":"20008_CR8","doi-asserted-by":"publisher","first-page":"116","DOI":"10.1186\/s13046-022-02306-4","volume":"41","author":"D Li","year":"2022","unstructured":"Li, D. et al. Cholesterol sensor SCAP contributes to sorafenib resistance by regulating autophagy in hepatocellular carcinoma. J. Exp. Clin. Cancer Res.: CR 41, 116. https:\/\/doi.org\/10.1186\/s13046-022-02306-4 (2022).","journal-title":"J. Exp. Clin. Cancer Res.: CR"},{"key":"20008_CR9","doi-asserted-by":"publisher","first-page":"98","DOI":"10.1186\/s13046-022-02296-3","volume":"41","author":"JK Byun","year":"2022","unstructured":"Byun, J. K. et al. Macropinocytosis is an alternative pathway of cysteine acquisition and mitigates sorafenib-induced ferroptosis in hepatocellular carcinoma. J. Exp. Clin. Cancer Res.: CR 41, 98. https:\/\/doi.org\/10.1186\/s13046-022-02296-3 (2022).","journal-title":"J. Exp. Clin. Cancer Res.: CR"},{"key":"20008_CR10","doi-asserted-by":"publisher","first-page":"e36282","DOI":"10.1016\/j.heliyon.2024.e36282","volume":"10","author":"H Zhang","year":"2024","unstructured":"Zhang, H. et al. miR-19a-3p promotes the growth of hepatocellular carcinoma by regulating p53\/SOX4. Heliyon 10, e36282. https:\/\/doi.org\/10.1016\/j.heliyon.2024.e36282 (2024).","journal-title":"Heliyon"},{"key":"20008_CR11","doi-asserted-by":"publisher","first-page":"145","DOI":"10.1186\/s13046-023-02718-w","volume":"42","author":"C Bergamini","year":"2023","unstructured":"Bergamini, C. et al. Induces metabolic changes through targeting and modulates sorafenib response in hepatocellular carcinoma. J. Exp. Clin. Cancer Res. 42, 145. https:\/\/doi.org\/10.1186\/s13046-023-02718-w (2023).","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"20008_CR12","doi-asserted-by":"publisher","first-page":"153","DOI":"10.1038\/s41419-025-07473-8","volume":"16","author":"Q Yang","year":"2025","unstructured":"Yang, Q. et al. Circulating mitochondrial DNA promotes M2 polarization of tumor associated macrophages and HCC resistance to sorafenib. Cell Death & Dis. 16, 153. https:\/\/doi.org\/10.1038\/s41419-025-07473-8 (2025).","journal-title":"Cell Death & Dis."},{"key":"20008_CR13","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1016\/j.semcancer.2021.04.003","volume":"85","author":"J Jiang","year":"2022","unstructured":"Jiang, J. Hedgehog signaling mechanism and role in cancer. Semin. Cancer Biol. 85, 107\u2013122. https:\/\/doi.org\/10.1016\/j.semcancer.2021.04.003 (2022).","journal-title":"Semin. Cancer Biol."},{"key":"20008_CR14","doi-asserted-by":"publisher","DOI":"10.3390\/life15020228","author":"S Iluta","year":"2025","unstructured":"Iluta, S. & Nistor, M. Notch and Hedgehog Signaling Unveiled: Crosstalk, Roles, and Breakthroughs in Cancer Stem Cell Research. Life https:\/\/doi.org\/10.3390\/life15020228 (2025).","journal-title":"Life"},{"key":"20008_CR15","doi-asserted-by":"publisher","first-page":"1554","DOI":"10.3390\/cancers7030851","volume":"7","author":"CR Cochrane","year":"2015","unstructured":"Cochrane, C. R., Szczepny, A., Watkins, D. N. & Cain, J. E. Hedgehog Signaling in the Maintenance of Cancer Stem Cells. Cancers 7, 1554\u20131585. https:\/\/doi.org\/10.3390\/cancers7030851 (2015).","journal-title":"Cancers"},{"key":"20008_CR16","doi-asserted-by":"publisher","first-page":"830","DOI":"10.1038\/s41419-023-06358-y","volume":"14","author":"S Chen","year":"2023","unstructured":"Chen, S. et al. The deubiquitinating enzyme USP44 suppresses hepatocellular carcinoma progression by inhibiting Hedgehog signaling and PDL1 expression. Cell Death & Dis. 14, 830. https:\/\/doi.org\/10.1038\/s41419-023-06358-y (2023).","journal-title":"Cell Death & Dis."},{"key":"20008_CR17","doi-asserted-by":"publisher","first-page":"3130","DOI":"10.1158\/1078-0432.ccr-09-2846","volume":"16","author":"AA Merchant","year":"2010","unstructured":"Merchant, A. A. & Matsui, W. Targeting Hedgehog\u2013a cancer stem cell pathway. Clin. Cancer Res.: Off. J. Am. Assoc. Cancer Res. 16, 3130\u20133140. https:\/\/doi.org\/10.1158\/1078-0432.ccr-09-2846 (2010).","journal-title":"Clin. Cancer Res.: Off. J. Am. Assoc. Cancer Res."},{"key":"20008_CR18","doi-asserted-by":"publisher","DOI":"10.3390\/ijms23031733","author":"NM Nguyen","year":"2022","unstructured":"Nguyen, N. M. & Cho, J. Hedgehog Pathway Inhibitors as Targeted Cancer Therapy and Strategies to Overcome Drug Resistance. Int. J. Mol. Sci. https:\/\/doi.org\/10.3390\/ijms23031733 (2022).","journal-title":"Int. J. Mol. Sci."},{"key":"20008_CR19","doi-asserted-by":"publisher","first-page":"172","DOI":"10.1186\/s12943-023-01877-w","volume":"22","author":"Z Zeng","year":"2023","unstructured":"Zeng, Z. et al. Regulation and signaling pathways in cancer stem cells: implications for targeted therapy for cancer. Mol. Cancer 22, 172. https:\/\/doi.org\/10.1186\/s12943-023-01877-w (2023).","journal-title":"Mol. Cancer"},{"key":"20008_CR20","doi-asserted-by":"publisher","first-page":"81","DOI":"10.1186\/s13046-021-01874-1","volume":"40","author":"Y Zhang","year":"2021","unstructured":"Zhang, Y. et al. Single-cell RNA sequencing in cancer research. J. Exp. Clin. Cancer Res.: CR 40, 81. https:\/\/doi.org\/10.1186\/s13046-021-01874-1 (2021).","journal-title":"J. Exp. Clin. Cancer Res.: CR"},{"key":"20008_CR21","doi-asserted-by":"publisher","first-page":"223","DOI":"10.1186\/s12967-023-04056-z","volume":"21","author":"Z Tan","year":"2023","unstructured":"Tan, Z. et al. Comprehensive analysis of scRNA-Seq and bulk RNA-Seq reveals dynamic changes in the tumor immune microenvironment of bladder cancer and establishes a prognostic model. J. Transl. Med. 21, 223. https:\/\/doi.org\/10.1186\/s12967-023-04056-z (2023).","journal-title":"J. Transl. Med."},{"key":"20008_CR22","doi-asserted-by":"publisher","first-page":"216664","DOI":"10.1016\/j.canlet.2024.216664","volume":"584","author":"L Ji","year":"2024","unstructured":"Ji, L. et al. scRNA-seq of colorectal cancer shows regional immune atlas with the function of CD20(+) B cells. Cancer Lett. 584, 216664. https:\/\/doi.org\/10.1016\/j.canlet.2024.216664 (2024).","journal-title":"Cancer Lett."},{"key":"20008_CR23","doi-asserted-by":"publisher","first-page":"329","DOI":"10.1002\/cac2.12078","volume":"40","author":"S Ding","year":"2020","unstructured":"Ding, S. & Chen, X. Single-cell RNA sequencing in breast cancer: Understanding tumor heterogeneity and paving roads to individualized therapy. Cancer Commun. 40, 329\u2013344. https:\/\/doi.org\/10.1002\/cac2.12078 (2020).","journal-title":"Cancer Commun."},{"key":"20008_CR24","doi-asserted-by":"publisher","first-page":"1096","DOI":"10.1016\/j.molcel.2020.04.027","volume":"78","author":"S Shu","year":"2020","unstructured":"Shu, S. et al. Synthetic Lethal and Resistance Interactions with BET Bromodomain Inhibitors in Triple-Negative Breast Cancer. Mol. Cell 78, 1096-1113.e1098. https:\/\/doi.org\/10.1016\/j.molcel.2020.04.027 (2020).","journal-title":"Mol. Cell"},{"key":"20008_CR25","doi-asserted-by":"publisher","first-page":"161","DOI":"10.1186\/s12916-023-02866-y","volume":"21","author":"T Wu","year":"2023","unstructured":"Wu, T. et al. Single-cell sequencing reveals the immune microenvironment landscape related to anti-PD-1 resistance in metastatic colorectal cancer with high microsatellite instability. BMC Med. 21, 161. https:\/\/doi.org\/10.1186\/s12916-023-02866-y (2023).","journal-title":"BMC Med."},{"key":"20008_CR26","doi-asserted-by":"publisher","first-page":"6494","DOI":"10.1038\/s41467-022-34277-7","volume":"13","author":"J Chen","year":"2022","unstructured":"Chen, J., Wang, X. & Ma, A. Deep transfer learning of cancer drug responses by integrating bulk and single-cell RNA-seq data. Nat. Commun. 13, 6494. https:\/\/doi.org\/10.1038\/s41467-022-34277-7 (2022).","journal-title":"Nat. Commun."},{"key":"20008_CR27","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1096\/fj.12-218222","volume":"27","author":"V Tirino","year":"2013","unstructured":"Tirino, V. et al. Cancer stem cells in solid tumors: an overview and new approaches for their isolation and characterization. FASEB J.: Off. Publ. Federation Am. Soc. Exp. Biol. 27, 13\u201324. https:\/\/doi.org\/10.1096\/fj.12-218222 (2013).","journal-title":"FASEB J.: Off. Publ. Federation Am. Soc. Exp. Biol."},{"key":"20008_CR28","doi-asserted-by":"publisher","first-page":"1185916","DOI":"10.3389\/fimmu.2023.1185916","volume":"14","author":"W Sun","year":"2023","unstructured":"Sun, W. et al. Combining WGCNA and machine learning to construct basement membrane-related gene index helps to predict the prognosis and tumor microenvironment of HCC patients and verifies the carcinogenesis of key gene CTSA. Front. Immunol. 14, 1185916. https:\/\/doi.org\/10.3389\/fimmu.2023.1185916 (2023).","journal-title":"Front. Immunol."},{"key":"20008_CR29","doi-asserted-by":"publisher","DOI":"10.1093\/bib\/bbab260","author":"D Maeser","year":"2021","unstructured":"Maeser, D., Gruener, R. F. & Huang, R. S. oncoPredict: an R package for predicting in vivo or cancer patient drug response and biomarkers from cell line screening data. Brief. Bioinform. https:\/\/doi.org\/10.1093\/bib\/bbab260 (2021).","journal-title":"Brief. Bioinform."},{"key":"20008_CR30","doi-asserted-by":"publisher","first-page":"762","DOI":"10.1038\/s41568-023-00612-3","volume":"23","author":"A Sajid","year":"2023","unstructured":"Sajid, A., Rahman, H. & Ambudkar, S. V. Advances in the structure, mechanism and targeting of chemoresistance-linked ABC transporters. Nat. Rev. Cancer 23, 762\u2013779. https:\/\/doi.org\/10.1038\/s41568-023-00612-3 (2023).","journal-title":"Nat. Rev. Cancer"},{"key":"20008_CR31","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.drup.2016.03.001","volume":"26","author":"JI Fletcher","year":"2016","unstructured":"Fletcher, J. I., Williams, R. T., Henderson, M. J., Norris, M. D. & Haber, M. ABC transporters as mediators of drug resistance and contributors to cancer cell biology. Drug Resistance Updates: Rev. Comment. Antimicrob. Anticancer Chemother. 26, 1\u20139. https:\/\/doi.org\/10.1016\/j.drup.2016.03.001 (2016).","journal-title":"Drug Resistance Updates: Rev. Comment. Antimicrob. Anticancer Chemother."},{"key":"20008_CR32","doi-asserted-by":"publisher","first-page":"452","DOI":"10.1038\/s41568-018-0005-8","volume":"18","author":"RW Robey","year":"2018","unstructured":"Robey, R. W., Pluchino, K. M. & Hall, M. D. Revisiting the role of ABC transporters in multidrug-resistant cancer. Nat. Rev. Cancer 18, 452\u2013464. https:\/\/doi.org\/10.1038\/s41568-018-0005-8 (2018).","journal-title":"Nat. Rev. Cancer"},{"key":"20008_CR33","doi-asserted-by":"publisher","first-page":"100905","DOI":"10.1016\/j.drup.2022.100905","volume":"66","author":"J Fan","year":"2023","unstructured":"Fan, J., To, K. K. W., Chen, Z. S. & Fu, L. ABC transporters affects tumor immune microenvironment to regulate cancer immunotherapy and multidrug resistance. Drug Resistance Updates: Rev. Comment. Antimicrob. Anticancer Chemother. 66, 100905. https:\/\/doi.org\/10.1016\/j.drup.2022.100905 (2023).","journal-title":"Drug Resistance Updates: Rev. Comment. Antimicrob. Anticancer Chemother."},{"key":"20008_CR34","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1016\/j.apsb.2020.09.016","volume":"11","author":"H Duan","year":"2021","unstructured":"Duan, H., Liu, Y., Gao, Z. & Huang, W. Recent advances in drug delivery systems for targeting cancer stem cells. Acta pharmaceutica Sinica. B 11, 55\u201370. https:\/\/doi.org\/10.1016\/j.apsb.2020.09.016 (2021).","journal-title":"Acta pharmaceutica Sinica. B"},{"key":"20008_CR35","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1016\/j.drup.2016.05.001","volume":"27","author":"W Li","year":"2016","unstructured":"Li, W. et al. Overcoming ABC transporter-mediated multidrug resistance: Molecular mechanisms and novel therapeutic drug strategies. Drug Resistance Updates: Rev. Comment. Antimicrob. Anticancer Chemother. 27, 14\u201329. https:\/\/doi.org\/10.1016\/j.drup.2016.05.001 (2016).","journal-title":"Drug Resistance Updates: Rev. Comment. Antimicrob. Anticancer Chemother."},{"key":"20008_CR36","doi-asserted-by":"publisher","first-page":"100743","DOI":"10.1016\/j.drup.2021.100743","volume":"54","author":"JQ Wang","year":"2021","unstructured":"Wang, J. Q. et al. Multidrug resistance proteins (MRPs): Structure, function and the overcoming of cancer multidrug resistance. Drug Resistance Updates: Rev. Comment. Antimicrob. Anticancer Chemother. 54, 100743. https:\/\/doi.org\/10.1016\/j.drup.2021.100743 (2021).","journal-title":"Drug Resistance Updates: Rev. Comment. Antimicrob. Anticancer Chemother."},{"key":"20008_CR37","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1186\/2001-1326-2-3","volume":"2","author":"LN Abdullah","year":"2013","unstructured":"Abdullah, L. N. & Chow, E. K. Mechanisms of chemoresistance in cancer stem cells. Clin. Transl. Med. 2, 3. https:\/\/doi.org\/10.1186\/2001-1326-2-3 (2013).","journal-title":"Clin. Transl. Med."},{"key":"20008_CR38","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1016\/j.canlet.2020.02.008","volume":"476","author":"HW Leung","year":"2020","unstructured":"Leung, H. W. et al. NRF2\/SHH signaling cascade promotes tumor-initiating cell lineage and drug resistance in hepatocellular carcinoma. Cancer Lett. 476, 48\u201356. https:\/\/doi.org\/10.1016\/j.canlet.2020.02.008 (2020).","journal-title":"Cancer Lett."},{"key":"20008_CR39","doi-asserted-by":"publisher","first-page":"1291","DOI":"10.1158\/1078-0432.ccr-11-0950","volume":"18","author":"Y Xu","year":"2012","unstructured":"Xu, Y. et al. Polymeric nanoparticle-encapsulated hedgehog pathway inhibitor HPI-1 (NanoHHI) inhibits systemic metastases in an orthotopic model of human hepatocellular carcinoma. Clin. Cancer Res.: Off. J. Am. Assoc. Cancer Res. 18, 1291\u20131302. https:\/\/doi.org\/10.1158\/1078-0432.ccr-11-0950 (2012).","journal-title":"Clin. Cancer Res.: Off. J. Am. Assoc. Cancer Res."},{"key":"20008_CR40","doi-asserted-by":"publisher","first-page":"939","DOI":"10.1080\/21691401.2020.1773484","volume":"48","author":"H Tian","year":"2020","unstructured":"Tian, H. & He, Z. Anti-hepatoma effect of taccalonolide A through suppression of sonic hedgehog pathway. Artif. Cells Nanomed. Biotechnol. 48, 939\u2013947. https:\/\/doi.org\/10.1080\/21691401.2020.1773484 (2020).","journal-title":"Artif. Cells Nanomed. Biotechnol."},{"key":"20008_CR41","doi-asserted-by":"publisher","first-page":"1238","DOI":"10.1124\/dmd.121.000704","volume":"50","author":"S Zhou","year":"2022","unstructured":"Zhou, S. & Shu, Y. Transcriptional Regulation of Solute Carrier (SLC) Drug Transporters. Drug Metab. Dispos. 50, 1238\u20131250. https:\/\/doi.org\/10.1124\/dmd.121.000704 (2022).","journal-title":"Drug Metab. Dispos."},{"key":"20008_CR42","doi-asserted-by":"publisher","first-page":"801","DOI":"10.1016\/j.tibs.2023.05.011","volume":"48","author":"A Schlessinger","year":"2023","unstructured":"Schlessinger, A., Zatorski, N., Hutchinson, K. & Colas, C. Targeting SLC transporters: small molecules as modulators and therapeutic opportunities. Trends Biochem. Sci. 48, 801\u2013814. https:\/\/doi.org\/10.1016\/j.tibs.2023.05.011 (2023).","journal-title":"Trends Biochem. Sci."},{"key":"20008_CR43","doi-asserted-by":"publisher","first-page":"469","DOI":"10.1038\/s41589-020-0483-3","volume":"16","author":"E Girardi","year":"2020","unstructured":"Girardi, E. et al. A widespread role for SLC transmembrane transporters in resistance to cytotoxic drugs. Nat. Chem. Biol. 16, 469\u2013478. https:\/\/doi.org\/10.1038\/s41589-020-0483-3 (2020).","journal-title":"Nat. Chem. Biol."},{"key":"20008_CR44","doi-asserted-by":"publisher","first-page":"493","DOI":"10.1080\/17425255.2020.1755253","volume":"16","author":"KM Huang","year":"2020","unstructured":"Huang, K. M. et al. Role of SLC transporters in toxicity induced by anticancer drugs. Expert Opin. Drug Metab. Toxicol. 16, 493\u2013506. https:\/\/doi.org\/10.1080\/17425255.2020.1755253 (2020).","journal-title":"Expert Opin. Drug Metab. Toxicol."},{"key":"20008_CR45","doi-asserted-by":"publisher","first-page":"2163","DOI":"10.1053\/j.gastro.2020.08.016","volume":"159","author":"CC Wong","year":"2020","unstructured":"Wong, C. C. et al. In Colorectal Cancer Cells With Mutant KRAS, SLC25A22-Mediated Glutaminolysis Reduces DNA Demethylation to Increase WNT Signaling, Stemness, and Drug Resistance. Gastroenterology 159, 2163-2180.e2166. https:\/\/doi.org\/10.1053\/j.gastro.2020.08.016 (2020).","journal-title":"Gastroenterology"},{"key":"20008_CR46","doi-asserted-by":"publisher","first-page":"113191","DOI":"10.1016\/j.celrep.2023.113191","volume":"42","author":"Y Audet-Delage","year":"2023","unstructured":"Audet-Delage, Y. et al. Spatiotemporal modeling of chemoresistance evolution in breast tumors uncovers dependencies on SLC38A7 and SLC46A1. Cell Rep. 42, 113191. https:\/\/doi.org\/10.1016\/j.celrep.2023.113191 (2023).","journal-title":"Cell Rep."},{"key":"20008_CR47","doi-asserted-by":"publisher","first-page":"616","DOI":"10.1016\/j.molcel.2023.12.037","volume":"84","author":"X Chen","year":"2024","unstructured":"Chen, X. & Gan, B. SLC25A39 links mitochondrial GSH sensing with iron metabolism. Mol. Cell 84, 616\u2013618. https:\/\/doi.org\/10.1016\/j.molcel.2023.12.037 (2024).","journal-title":"Mol. Cell"},{"key":"20008_CR48","doi-asserted-by":"publisher","first-page":"136","DOI":"10.1038\/s41586-021-04025-w","volume":"599","author":"Y Wang","year":"2021","unstructured":"Wang, Y. & Yen, F. S. SLC25A39 is necessary for mitochondrial glutathione import in mammalian cells. Nature 599, 136\u2013140. https:\/\/doi.org\/10.1038\/s41586-021-04025-w (2021).","journal-title":"Nature"},{"key":"20008_CR49","doi-asserted-by":"publisher","first-page":"2483","DOI":"10.1038\/s41467-022-30126-9","volume":"13","author":"X Shi","year":"2022","unstructured":"Shi, X. & Reinstadler, B. Combinatorial GxGxE CRISPR screen identifies SLC25A39 in mitochondrial glutathione transport linking iron homeostasis to OXPHOS. Nat. Commun. 13, 2483. https:\/\/doi.org\/10.1038\/s41467-022-30126-9 (2022).","journal-title":"Nat. Commun."},{"key":"20008_CR50","doi-asserted-by":"publisher","first-page":"519","DOI":"10.1038\/s41419-023-06045-y","volume":"14","author":"Y Liu","year":"2023","unstructured":"Liu, Y., Lu, S. & Wu, L. L. The diversified role of mitochondria in ferroptosis in cancer. Cell death Dis. 14, 519. https:\/\/doi.org\/10.1038\/s41419-023-06045-y (2023).","journal-title":"Cell death Dis."},{"key":"20008_CR51","doi-asserted-by":"publisher","first-page":"909","DOI":"10.1016\/j.jhep.2019.12.015","volume":"72","author":"W Dai","year":"2020","unstructured":"Dai, W. et al. OGDHL silencing promotes hepatocellular carcinoma by reprogramming glutamine metabolism. J. Hepatol. 72, 909\u2013923. https:\/\/doi.org\/10.1016\/j.jhep.2019.12.015 (2020).","journal-title":"J. Hepatol."},{"key":"20008_CR52","doi-asserted-by":"publisher","first-page":"792","DOI":"10.1111\/cas.16417","volume":"116","author":"Y Chen","year":"2025","unstructured":"Chen, Y. et al. Tumor exosomal RNPEP promotes lung metastasis of liver cancer via inducing cancer-associated fibroblast activation. Cancer Sci. 116, 792\u2013807. https:\/\/doi.org\/10.1111\/cas.16417 (2025).","journal-title":"Cancer Sci."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-20008-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-20008-7","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-20008-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,15]],"date-time":"2025-10-15T11:14:23Z","timestamp":1760526863000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-20008-7"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,15]]},"references-count":52,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["20008"],"URL":"https:\/\/doi.org\/10.1038\/s41598-025-20008-7","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,15]]},"assertion":[{"value":"18 May 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"11 September 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"15 October 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare no competing interests.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"The studies involving humans were approved by Biomedical Ethics Committee of Anhui Medical University (LLSC2020979). The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study. The animal study was approved by Laboratory Animal Ethics Committee of Anhui Medical University (LLSC20200965), and use guidelines of the National Institutes of Health, USA. The animal study has been reported in the manuscript in accordance with ARRIVE guidelines. The study was conducted in accordance with the local legislation and institutional requirements.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics"}}],"article-number":"36061"}}