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(Landmark Ed)"],"abstract":"<jats:p>Background:Cysteinyl-tRNA synthetase 1 (CARS1) has been included in ferroptosis-related prognostic signatures, but its clinicopathological relevance, cellular functions, and relationship with the immune microenvironment in hepatocellular carcinoma (HCC) remain incompletely characterized.Methods:Transcriptomic and clinical data from The Cancer Genome Atlas Liver Hepatocellular Carcinoma (TCGA-LIHC) dataset were integrated with corresponding data from an institutional HCC tissue cohort of 60 patients. CARS1 expression was evaluated by immunohistochemistry, and immune infiltration was examined using single-sample gene-set enrichment analysis (ssGSEA) and multiplex immunofluorescence, as well as by analyzing public single-cell datasets. The effects of CARS1 depletion were evaluated in MHCC97H and Hep3B cells using Cell Counting Kit-8 (CCK-8) assays, cell-cycle profiling, wound-healing assays, Transwell migration assays, western blotting, and erlotinib-sensitivity assays.Results:CARS1 expression was elevated in HCC and was associated with adverse clinicopathological features and poor overall survival. Quantitative immunohistochemistry confirmed elevated CARS1 protein expression in tumor tissues. CARS1 depletion inhibited cell proliferation, altered cell-cycle distribution, impaired migration, and enhanced in vitro sensitivity to erlotinib. High CARS1 expression was also associated with increased infiltration of Th2-like immune cells.Conclusions:Elevated CARS1 expression is associated with an adverse biological and immune phenotype in HCC. These clinical, histopathological, and loss-of-function findings support further investigation of CARS1 as a prognostic marker and candidate therapeutic target in HCC, although additional mechanistic and in vivo validation is required.<\/jats:p>","DOI":"10.31083\/fbl53642","type":"journal-article","created":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T12:35:31Z","timestamp":1788438931000},"source":"Crossref","is-referenced-by-count":0,"title":["CARS1 as a Prognostic Biomarker and Candidate Therapeutic Vulnerability in Hepatocellular Carcinoma: Insights Into Tumor Progression and the Immune Microenvironment"],"prefix":"10.31083","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-6389-4679","authenticated-orcid":true,"given":"Yezhen","family":"Tang","sequence":"first","affiliation":[{"name":"School of Basic Medicine, Ningxia Medical University, 750004 Yinchuan, Ningxia, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5770-7865","authenticated-orcid":true,"given":"Kejun","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary Surgery, General Hospital of Ningxia Medical University, 750004 Yinchuan, Ningxia, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-8239-3718","authenticated-orcid":true,"given":"Zhenyao","family":"Tan","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary Surgery, General Hospital of Ningxia Medical University, 750004 Yinchuan, Ningxia, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5245-1351","authenticated-orcid":true,"given":"Wei","family":"Zhao","sequence":"additional","affiliation":[{"name":"School of Basic Medicine, Ningxia Medical University, 750004 Yinchuan, Ningxia, China"},{"name":"Ningxia Institute of Clinical Medicine, Ningxia People\u2019s Hospital, Ningxia Medical University, 750002 Yinchuan, Ningxia, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"16242","published-online":{"date-parts":[[2026,8,17]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","unstructured":"Bray F, Laversanne M, Sung H, Ferlay J, Siegel RL, Soerjomataram I, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: a Cancer Journal for Clinicians. 2024; 74: 229\u2013263.","DOI":"10.3322\/caac.21834"},{"key":"ref2","doi-asserted-by":"publisher","unstructured":"Singal AG, Llovet JM, Yarchoan M, Mehta N, Heimbach JK, Dawson LA, et al. AASLD Practice Guidance on prevention, diagnosis, and treatment of hepatocellular carcinoma. Hepatology (Baltimore, Md.). 2023; 78: 1922\u20131965.","DOI":"10.1097\/HEP.0000000000000466"},{"key":"ref3","doi-asserted-by":"publisher","unstructured":"European Association for the Study of the Liver. EASL Clinical Practice Guidelines on the management of hepatocellular carcinoma. Journal of Hepatology. 2025; 82: 315\u2013374.","DOI":"10.1016\/j.jhep.2024.08.028"},{"key":"ref4","doi-asserted-by":"publisher","unstructured":"Hayano M, Yang WS, Corn CK, Pagano NC, Stockwell BR. Loss of cysteinyl-tRNA synthetase (CARS) induces the transsulfuration pathway and inhibits ferroptosis induced by cystine deprivation. Cell Death and Differentiation. 2016; 23: 270\u2013278.","DOI":"10.1038\/cdd.2015.93"},{"key":"ref5","doi-asserted-by":"publisher","unstructured":"Zhang W, Lin X, Chen S. Cysteinyl-tRNA Synthetase 1 Promotes Ferroptosis-Induced Cell Death via Regulating GPX4 Expression. Journal of Oncology. 2022; 2022: 4849174.","DOI":"10.1155\/2022\/4849174"},{"key":"ref6","doi-asserted-by":"publisher","unstructured":"Cho S, Kim SB, Lee Y, Song EC, Kim U, Kim HY, et al. Endogenous TLR2 ligand embedded in the catalytic region of human cysteinyl-tRNA synthetase 1. Journal for Immunotherapy of Cancer. 2020; 8: e000277.","DOI":"10.1136\/jitc-2019-000277"},{"key":"ref7","doi-asserted-by":"publisher","unstructured":"Yuan M, Yan R, Zhang Y, Qiu Y, Jiang Z, Liu H, et al. CARS senses cysteine deprivation to activate AMPK for cell survival. The EMBO Journal. 2021; 40: e108028.","DOI":"10.15252\/embj.2021108028"},{"key":"ref8","doi-asserted-by":"publisher","unstructured":"Kim HY, Cho S, Kim SB, Song EC, Jung W, Shin YG, et al. Specific targeting of cancer vaccines to antigen-presenting cells via an endogenous TLR2\/6 ligand derived from cysteinyl-tRNA synthetase 1. Molecular Therapy: the Journal of the American Society of Gene Therapy. 2024; 32: 3597\u20133617.","DOI":"10.1016\/j.ymthe.2024.07.014"},{"key":"ref9","doi-asserted-by":"publisher","unstructured":"Tang B, Zhu J, Li J, Fan K, Gao Y, Cheng S, et al. The ferroptosis and iron-metabolism signature robustly predicts clinical diagnosis, prognosis and immune microenvironment for hepatocellular carcinoma. Cell Communication and Signaling: CCS. 2020; 18: 174.","DOI":"10.1186\/s12964-020-00663-1"},{"key":"ref10","doi-asserted-by":"publisher","unstructured":"Hu Y, Chen D, Hong M, Liu J, Li Y, Hao J, et al. Apoptosis, Pyroptosis, and Ferroptosis Conspiringly Induce Immunosuppressive Hepatocellular Carcinoma Microenvironment and \u03b3\u03b4 T-Cell Imbalance. Frontiers in Immunology. 2022; 13: 845974.","DOI":"10.3389\/fimmu.2022.845974"},{"key":"ref11","doi-asserted-by":"publisher","unstructured":"Cancer Genome Atlas Research Network. Comprehensive and Integrative Genomic Characterization of Hepatocellular Carcinoma. Cell. 2017; 169: 1327\u20131341.e23.","DOI":"10.1016\/j.cell.2017.05.046"},{"key":"ref12","doi-asserted-by":"publisher","unstructured":"Uhl\u00e9n M, Fagerberg L, Hallstr\u00f6m BM, Lindskog C, Oksvold P, Mardinoglu A, et al. Proteomics. Tissue-based map of the human proteome. Science (New York, N.Y.). 2015; 347: 1260419.","DOI":"10.1126\/science.1260419"},{"key":"ref13","doi-asserted-by":"publisher","unstructured":"Wu T, Hu E, Xu S, Chen M, Guo P, Dai Z, et al. clusterProfiler 4.0: A universal enrichment tool for interpreting omics data. Innovation (Cambridge (Mass.)). 2021; 2: 100141.","DOI":"10.1016\/j.xinn.2021.100141"},{"key":"ref14","doi-asserted-by":"publisher","unstructured":"Szklarczyk D, Nastou K, Koutrouli M, Kirsch R, Mehryary F, Hachilif R, et al. The STRING database in 2025: protein networks with directionality of regulation. Nucleic Acids Research. 2025; 53: D730\u2013D737.","DOI":"10.1093\/nar\/gkae1113"},{"key":"ref15","doi-asserted-by":"publisher","unstructured":"H\u00e4nzelmann S, Castelo R, Guinney J. GSVA: gene set variation analysis for microarray and RNA-seq data. BMC Bioinformatics. 2013; 14: 7.","DOI":"10.1186\/1471-2105-14-7"},{"key":"ref16","doi-asserted-by":"publisher","unstructured":"Bindea G, Mlecnik B, Tosolini M, Kirilovsky A, Waldner M, Obenauf AC, et al. Spatiotemporal dynamics of intratumoral immune cells reveal the immune landscape in human cancer. Immunity. 2013; 39: 782\u2013795.","DOI":"10.1016\/j.immuni.2013.10.003"},{"key":"ref17","doi-asserted-by":"publisher","unstructured":"Hao Y, Hao S, Andersen-Nissen E, Mauck WM III, Zheng S, Butler A, et al. Integrated analysis of multimodal single-cell data. Cell. 2021; 184: 3573\u20133587.e29.","DOI":"10.1016\/j.cell.2021.04.048"},{"key":"ref18","doi-asserted-by":"publisher","unstructured":"Geeleher P, Cox N, Huang RS. pRRophetic: an R package for prediction of clinical chemotherapeutic response from tumor gene expression levels. PLoS ONE. 2014; 9: e107468.","DOI":"10.1371\/journal.pone.0107468"},{"key":"ref19","doi-asserted-by":"publisher","unstructured":"Lu X, Chen J, Lu Z, Zang H. Knockdown of PAK1IP1 can Induce Pyroptosis to inhibit the Progression of Hepatocellular Carcinoma. Frontiers in Bioscience (Landmark Edition). 2025; 30: 26654.","DOI":"10.31083\/FBL26654"},{"key":"ref20","doi-asserted-by":"publisher","unstructured":"Zheng W, Flavell RA. The transcription factor GATA-3 is necessary and sufficient for th2 cytokine gene expression in CD4 t cells. Cell. 1997; 89: 587\u2013596.","DOI":"10.1016\/S0092-8674(00)80240-8"},{"key":"ref21","doi-asserted-by":"publisher","unstructured":"Sia D, Jiao Y, Martinez-Quetglas I, Kuchuk O, Villacorta-Martin C, Castro de Moura M, et al. Identification of an Immune-specific Class of Hepatocellular Carcinoma, Based on Molecular Features. Gastroenterology. 2017; 153: 812\u2013826.","DOI":"10.1053\/j.gastro.2017.06.007"},{"key":"ref22","doi-asserted-by":"publisher","unstructured":"Li M, Wang L, Cong L, Wong CC, Zhang X, Chen H, et al. Spatial proteomics of immune microenvironment in nonalcoholic steatohepatitis-associated hepatocellular carcinoma. Hepatology (Baltimore, Md.). 2024; 79: 560\u2013574.","DOI":"10.1097\/HEP.0000000000000591"},{"key":"ref23","doi-asserted-by":"publisher","unstructured":"Sali\u00e9 H, Wischer L, D'Alessio A, Godbole I, Suo Y, Otto-Mora P, et al. Spatial single-cell profiling and neighbourhood analysis reveal the determinants of immune architecture connected to checkpoint inhibitor therapy outcome in hepatocellular carcinoma. Gut. 2025; 74: 451\u2013466.","DOI":"10.1136\/gutjnl-2024-332837"},{"key":"ref24","doi-asserted-by":"publisher","unstructured":"Zhou C, Wu YL, Chen G, Feng J, Liu XQ, Wang C, et al. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. The Lancet. Oncology. 2011; 12: 735\u2013742.","DOI":"10.1016\/S1470-2045(11)70184-X"},{"key":"ref25","doi-asserted-by":"publisher","unstructured":"Philip PA, Mahoney MR, Allmer C, Thomas J, Pitot HC, Kim G, et al. Phase II study of Erlotinib (OSI-774) in patients with advanced hepatocellular cancer. Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology. 2005; 23: 6657\u20136663.","DOI":"10.1200\/JCO.2005.14.696"},{"key":"ref26","doi-asserted-by":"publisher","unstructured":"Zhu AX, Rosmorduc O, Evans TRJ, Ross PJ, Santoro A, Carrilho FJ, et al. SEARCH: a phase III, randomized, double-blind, placebo-controlled trial of sorafenib plus erlotinib in patients with advanced hepatocellular carcinoma. Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology. 2015; 33: 559\u2013566.","DOI":"10.1200\/JCO.2013.53.7746"},{"key":"ref27","doi-asserted-by":"publisher","unstructured":"Cui L, Liu J, Lv Y, Chen B, Liu K, Bu Y. Study on the Mechanism of CCN2 Promoting Sorafenib Resistance in HCC and Its Combined Intervention Strategy. Frontiers in Bioscience (Landmark Edition). 2025; 30: 45454.","DOI":"10.31083\/FBL45454"},{"key":"ref28","doi-asserted-by":"publisher","unstructured":"Zhao J, Li M, Xu J, Cheng W. The modulation of ion channels in cancer chemo-resistance. Frontiers in Oncology. 2022; 12: 945896.","DOI":"10.3389\/fonc.2022.945896"},{"key":"ref29","doi-asserted-by":"publisher","unstructured":"Wong KK, Banham AH, Yaacob NS, Nur Husna SM. The oncogenic roles of TRPM ion channels in cancer. 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