{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T11:21:39Z","timestamp":1785410499152,"version":"3.56.0"},"reference-count":67,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2026,5,2]],"date-time":"2026-05-02T00:00:00Z","timestamp":1777680000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006245","name":"Noncommunicable Chronic Diseases-National Science and Technology Major Project","doi-asserted-by":"publisher","award":["2024ZD0531100"],"award-info":[{"award-number":["2024ZD0531100"]}],"id":[{"id":"10.13039\/501100006245","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["22004082"],"award-info":[{"award-number":["22004082"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"award":["22004082"],"award-info":[{"award-number":["22004082"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006245","name":"National Key R&D Program of China","doi-asserted-by":"publisher","award":["2023YFC3402800"],"award-info":[{"award-number":["2023YFC3402800"]}],"id":[{"id":"10.13039\/501100006245","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100013318","name":"Fundamental Research Program of Shanxi Province","doi-asserted-by":"publisher","award":["202503021211127"],"award-info":[{"award-number":["202503021211127"]}],"id":[{"id":"10.13039\/501100013318","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100013318","name":"Fundamental Research Program of Shanxi Province","doi-asserted-by":"publisher","award":["202503021212345"],"award-info":[{"award-number":["202503021212345"]}],"id":[{"id":"10.13039\/501100013318","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Shanxi Medical University Doctoral Start-up Fund Project","award":["XD1907"],"award-info":[{"award-number":["XD1907"]}]},{"DOI":"10.13039\/501100013794","name":"Scientific and Technological Innovation Programs of Higher Education Institutions in Shanxi","doi-asserted-by":"publisher","award":["2025Q013"],"award-info":[{"award-number":["2025Q013"]}],"id":[{"id":"10.13039\/501100013794","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100013794","name":"Scientific and Technological Innovation Programs of Higher Education Institutions in Shanxi","doi-asserted-by":"publisher","award":["2025L040"],"award-info":[{"award-number":["2025L040"]}],"id":[{"id":"10.13039\/501100013794","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Although sorafenib (SOR) is effective for advanced hepatocellular carcinoma (HCC), significant metabolic heterogeneity limits its therapeutic effect. In this study, we employed high-resolution matrix-assisted laser desorption\/ionization mass spectrometry imaging (MALDI MSI) to profile the spatial lipidomic alterations in 3D HepG2 spheroids following SOR treatment. Interestingly, sphingophospholipid and glycerophospholipid metabolism played crucial roles. In an orthotopic HCC mouse model, immunohistochemical and immunofluorescence staining confirmed that SOR induced immunological and inflammatory changes. Moreover, transcriptomic and Q-PCR analyses showed increased expression of Stat1, Zbp1, Parp14, Irf1, and Tifa along with decreased Eif4e2 in the SOR treatment group compared to the tumor control group. Bio-layer interferometry and molecular docking data also indicated that ZBP1 possessed favorable binding affinities with SOR. Overall, our findings demonstrated that SOR dramatically disrupted sphingolipid metabolism in tumor cell spheroids and, in an orthotopic model, activated the NOD-like receptor signaling pathway, accompanied by altered secretion of inflammatory factors and macrophage polarization. These results suggest that SOR exerts dual effects on tumor cell lipid metabolism and the tumor immune microenvironment. These findings provide a conceptual basis for future exploration of lipid-modulating therapeutic strategies in HCC.<\/jats:p>","DOI":"10.3390\/biom16050675","type":"journal-article","created":{"date-parts":[[2026,5,4]],"date-time":"2026-05-04T02:06:21Z","timestamp":1777860381000},"page":"675","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Deciphering Lipid Metabolic Landscape of Sorafenib-Treated Hepatocellular Carcinoma by Mass Spectrometry Imaging and Transcriptomics"],"prefix":"10.3390","volume":"16","author":[{"given":"Dongsheng","family":"Li","sequence":"first","affiliation":[{"name":"First Clinical Medical School, Shanxi Medical University, Taiyuan 030001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanyuan","family":"Tuo","sequence":"additional","affiliation":[{"name":"School of Basic Medical Sciences, Academy of Medical Sciences, Research Institute of Circadian Rhythm and Disease, Shanxi Medical University, Taiyuan 030001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luheng","family":"Sai","sequence":"additional","affiliation":[{"name":"School of Basic Medical Sciences, Academy of Medical Sciences, Research Institute of Circadian Rhythm and Disease, Shanxi Medical University, Taiyuan 030001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiunan","family":"Xu","sequence":"additional","affiliation":[{"name":"School of Basic Medical Sciences, Academy of Medical Sciences, Research Institute of Circadian Rhythm and Disease, Shanxi Medical University, Taiyuan 030001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fujuan","family":"Peng","sequence":"additional","affiliation":[{"name":"School of Basic Medical Sciences, Academy of Medical Sciences, Research Institute of Circadian Rhythm and Disease, Shanxi Medical University, Taiyuan 030001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhipeng","family":"Yan","sequence":"additional","affiliation":[{"name":"Shanxi Provincial People\u2019s Hospital, Fifth Hospital of Shanxi Medical University, Taiyuan 030012, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qin","family":"Yang","sequence":"additional","affiliation":[{"name":"Shanxi Provincial People\u2019s Hospital, Fifth Hospital of Shanxi Medical University, Taiyuan 030012, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huifang","family":"Zhao","sequence":"additional","affiliation":[{"name":"School of Basic Medical Sciences, Academy of Medical Sciences, Research Institute of Circadian Rhythm and Disease, Shanxi Medical University, Taiyuan 030001, China"},{"name":"Shanxi Provincial People\u2019s Hospital, Fifth Hospital of Shanxi Medical University, Taiyuan 030012, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6922-0747","authenticated-orcid":false,"given":"Ruiping","family":"Zhang","sequence":"additional","affiliation":[{"name":"Shanxi Provincial People\u2019s Hospital, Fifth Hospital of Shanxi Medical University, Taiyuan 030012, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1016\/j.semcancer.2021.02.015","article-title":"Cellular heterogeneity and plasticity in liver cancer","volume":"82","author":"Chan","year":"2022","journal-title":"Semin. Cancer Biol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1105","DOI":"10.1038\/s41417-024-00764-w","article-title":"Heterogeneity of hepatocellular carcinoma: From mechanisms to clinical implications","volume":"31","author":"Safri","year":"2024","journal-title":"Cancer Gene Ther."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2161","DOI":"10.1002\/cbin.11670","article-title":"Targeting molecular signal transduction pathways in hepatocellular carcinoma and its implications for cancer therapy","volume":"45","author":"Mir","year":"2021","journal-title":"Cell Biol. Int."},{"key":"ref_4","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."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"102434","DOI":"10.1016\/j.clinre.2024.102434","article-title":"Mechanisms of sorafenib resistance in hepatocellular carcinoma","volume":"48","author":"Liang","year":"2024","journal-title":"Clin. Res. Hepatol. Gastroenterol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"217061","DOI":"10.1016\/j.canlet.2024.217061","article-title":"Hepatocellular carcinoma and lipid metabolism: Novel targets and therapeutic strategies","volume":"597","author":"Cao","year":"2024","journal-title":"Cancer Lett."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1038\/s12276-025-01415-2","article-title":"Metabolic reprogramming in hepatocellular carcinoma: Mechanisms and therapeutic implications","volume":"57","author":"Park","year":"2025","journal-title":"Exp. Mol. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"669","DOI":"10.1002\/hep.1840180327","article-title":"Fatty-acid metabolism and the pathogenesis of hepatocellular carcinoma: Review and hypothesis","volume":"18","author":"Ockner","year":"1993","journal-title":"Hepatology"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"10089","DOI":"10.1096\/fj.201802619RR","article-title":"Sorafenib kills liver cancer cells by disrupting SCD1-mediated synthesis of monounsaturated fatty acids via the ATP-AMPK-mTOR-SREBP1 signaling pathway","volume":"33","author":"Liu","year":"2019","journal-title":"FASEB J."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1002\/cbin.10911","article-title":"Metabolic profiling of normal hepatocyte and hepatocellular carcinoma cells via 1 H nuclear magnetic resonance spectroscopy","volume":"42","author":"Chen","year":"2018","journal-title":"Cell Biol. Int."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1016\/j.jchromb.2014.01.057","article-title":"Metabolic profiling study of early and late recurrence of hepatocellular carcinoma based on liquid chromatography-mass spectrometry","volume":"966","author":"Zhou","year":"2014","journal-title":"J. Chromatogr. B Anal. Technol. Biomed. Life Sci."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Geyer, T., R\u00fcbenthaler, J., Alunni-Fabbroni, M., Schinner, R., Weber, S., Mayerle, J., Schiffer, E., H\u00f6ckner, S., Malfertheiner, P., and Ricke, J. (2021). NMR-Based Lipid Metabolite Profiles to Predict Outcomes in Patients Undergoing Interventional Therapy for a Hepatocellular Carcinoma (HCC): A Substudy of the SORAMIC Trial. Cancers, 13.","DOI":"10.3390\/cancers13112787"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Erlmeier, F., Sun, N., Shen, J., Feuchtinger, A., Buck, A., Prade, V.M., Kunzke, T., Schraml, P., Moch, H., and Autenrieth, M. (2022). MALDI Mass Spectrometry Imaging\u2014Prognostic Pathways and Metabolites for Renal Cell Carcinomas. Cancers, 14.","DOI":"10.3390\/cancers14071763"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Torres, M., Gruer, L., Valsaraj, S., Reece, S., Prokop, J., Zeczycki, T., Taylor, C., Byers, T., Cruz, W., and Kew, K. (2025). Relative Quantitation of EFNA1 Expression in Mouse Heart Tissue Histologic Sections Using MALDI-MSI. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26041398"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"893","DOI":"10.3892\/ijo.2014.2788","article-title":"MALDI TOF imaging mass spectrometry in clinical pathology: A valuable tool for cancer diagnostics (review)","volume":"46","author":"Kriegsmann","year":"2015","journal-title":"Int. J. Oncol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"13667","DOI":"10.1021\/acs.analchem.2c00768","article-title":"Three-Dimensional Mass Spectrometry Imaging Reveals Distributions of Lipids and the Drug Metabolite Associated with the Enhanced Growth of Colon Cancer Cell Spheroids Treated with Triclosan","volume":"94","author":"Xie","year":"2022","journal-title":"Anal. Chem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"3407","DOI":"10.1039\/D5AY00022J","article-title":"Preparation of multicellular spheroid sections embedded with sodium carboxymethyl cellulose for mass spectrometry imaging","volume":"17","author":"Wang","year":"2025","journal-title":"Anal. Methods"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1080\/08830185.2019.1645138","article-title":"The role of pro-inflammatory cytokines in lipid metabolism of metabolic diseases","volume":"38","author":"Chen","year":"2019","journal-title":"Int. Rev. Immunol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.jnutbio.2015.11.002","article-title":"Role of lipids in the metabolism and activation of immune cells","volume":"34","author":"Hubler","year":"2016","journal-title":"J. Nutr. Biochem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"115927","DOI":"10.1016\/j.bios.2023.115927","article-title":"An ultrasensitive and multiplexed miRNA one-step real time RT-qPCR detection system and its application in esophageal cancer serum","volume":"247","author":"Xue","year":"2024","journal-title":"Biosens. Bioelectron."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Huang, J., Chen, W., Jie, Z., and Jiang, M. (2022). Comprehensive Analysis of Immune Implications and Prognostic Value of SPI1 in Gastric Cancer. Front. Oncol., 12.","DOI":"10.3389\/fonc.2022.820568"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"e321","DOI":"10.1038\/tp.2013.94","article-title":"Gene expression profiling by mRNA sequencing reveals increased expression of immune\/inflammation-related genes in the hippocampus of individuals with schizophrenia","volume":"3","author":"Hwang","year":"2013","journal-title":"Transl. Psychiatry"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"e15070","DOI":"10.7717\/peerj.15070","article-title":"PAIP1 regulates expression of immune and inflammatory response associated genes at transcript level in liver cancer cell","volume":"11","author":"Zheng","year":"2023","journal-title":"PeerJ"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Holubekova, V., Loderer, D., Grendar, M., Mikolajcik, P., Kolkova, Z., Turyova, E., Kudelova, E., Kalman, M., Marcinek, J., and Miklusica, J. (2023). Differential gene expression of immunity and inflammation genes in colorectal cancer using targeted RNA sequencing. Front. Oncol., 13.","DOI":"10.3389\/fonc.2023.1206482"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"10221","DOI":"10.1021\/acs.analchem.3c00479","article-title":"In Situ Spatial Analysis of Metabolic Heterogeneity in Single Living Tumor Spheroids Using Nanocapillary-Based Electrospray Ionization Mass Spectroscopy","volume":"95","author":"Xia","year":"2023","journal-title":"Anal. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1988","DOI":"10.1038\/s41416-021-01363-4","article-title":"\u03b1-Fetoprotein mRNA in situ hybridisation is a highly specific marker of hepatocellular carcinoma: A multi-centre study","volume":"124","author":"Lu","year":"2021","journal-title":"Br. J. Cancer"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"114391","DOI":"10.1016\/j.yexcr.2024.114391","article-title":"GPC-3 in hepatocellular carcinoma; A novel biomarker and molecular target","volume":"444","author":"Tehrani","year":"2025","journal-title":"Exp. Cell Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1111\/j.1440-1746.1998.01555.x","article-title":"Ki-67 expression as a prognostic marker in patients with hepatocellular carcinoma","volume":"13","author":"King","year":"1998","journal-title":"J. Gastroenterol. Hepatol."},{"key":"ref_29","first-page":"221","article-title":"Reduced glutathione system: Role in cancer development, prevention and treatment (review)","volume":"19","author":"Locigno","year":"2001","journal-title":"Int. J. Oncol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1016\/0959-8049(95)00531-5","article-title":"Role of oxygen free radicals in cancer development","volume":"32","author":"Dreher","year":"1996","journal-title":"Eur. J. Cancer"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1186\/s13046-016-0478-9","article-title":"FGF19\/FGFR4 signaling contributes to the resistance of hepatocellular carcinoma to sorafenib","volume":"36","author":"Gao","year":"2017","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_32","first-page":"4867730","article-title":"The Emerging Role of MTHFD Family Genes in Regulating the Tumor Immunity of Oral Squamous Cell Carcinoma","volume":"2022","author":"Wang","year":"2022","journal-title":"J. Oncol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"3624","DOI":"10.1038\/s41467-020-17177-6","article-title":"MG53 suppresses interferon-\u03b2 and inflammation via regulation of ryanodine receptor-mediated intracellular calcium signaling","volume":"11","author":"Sermersheim","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"e569","DOI":"10.1002\/cpz1.569","article-title":"Assessment of Antitumor and Antiproliferative Efficacy and Detection of Protein-Protein Interactions in Cancer Cells from 3D Tumor Spheroids","volume":"2","author":"Sonju","year":"2022","journal-title":"Curr. Protoc."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"3352","DOI":"10.1364\/BOE.425512","article-title":"Characterization and quantification of necrotic tissues and morphology in multicellular ovarian cancer tumor spheroids using optical coherence tomography","volume":"12","author":"Yan","year":"2021","journal-title":"Biomed. Opt. Express"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Zhakupova, A., Zeinolla, A., Kokabi, K., Sergazy, S., and Aljofan, M. (2025). Drug Resistance: The Role of Sphingolipid Metabolism. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26083716"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Ohshima, K., and Morii, E. (2021). Metabolic Reprogramming of Cancer Cells during Tumor Progression and Metastasis. Metabolites, 11.","DOI":"10.3390\/metabo11010028"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1016\/j.cell.2011.02.013","article-title":"Hallmarks of cancer: The next generation","volume":"144","author":"Hanahan","year":"2011","journal-title":"Cell"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1016\/j.cmet.2013.08.002","article-title":"A Central role for mTOR in lipid homeostasis","volume":"18","author":"Lamming","year":"2013","journal-title":"Cell Metab."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Wang, Z., Wang, Y., Li, Z., Xue, W., Hu, S., and Kong, X. (2023). Lipid metabolism as a target for cancer drug resistance: Progress and prospects. Front. Pharmacol., 14.","DOI":"10.3389\/fphar.2023.1274335"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"888","DOI":"10.1016\/j.bbamem.2006.09.012","article-title":"Dynamic phospholipid signaling by G protein-coupled receptors","volume":"1768","author":"Han","year":"2007","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"123165","DOI":"10.1016\/j.lfs.2024.123165","article-title":"Integration of network pharmacology, metabolomics and lipidomics for clarifying the role of sphingolipid metabolism in the treatment of liver cancer by regorafenib","volume":"358","author":"Mu","year":"2024","journal-title":"Life Sci."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1038\/s41392-020-0187-x","article-title":"The mechanisms of sorafenib resistance in hepatocellular carcinoma: Theoretical basis and therapeutic aspects","volume":"5","author":"Tang","year":"2020","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1186\/s12943-019-1089-9","article-title":"Role of hypoxia in cancer therapy by regulating the tumor microenvironment","volume":"18","author":"Jing","year":"2019","journal-title":"Mol. Cancer"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1054\/drup.2000.0119","article-title":"pH and drug resistance in tumors","volume":"3","author":"Raghunand","year":"2000","journal-title":"Drug Resist. Updates"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"e12772","DOI":"10.1111\/cpr.12772","article-title":"Aberrant lipid metabolism in hepatocellular carcinoma cells as well as immune microenvironment: A review","volume":"53","author":"Hu","year":"2020","journal-title":"Cell Prolif."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Wang, D., Ye, Q., Gu, H., and Chen, Z. (2022). The role of lipid metabolism in tumor immune microenvironment and potential therapeutic strategies. Front. Oncol., 12.","DOI":"10.3389\/fonc.2022.984560"},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Florance, I., and Ramasubbu, S. (2022). Current Understanding on the Role of Lipids in Macrophages and Associated Diseases. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24010589"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1186\/s13578-024-01201-z","article-title":"Macrophage heterogeneity and its interactions with stromal cells in tumour microenvironment","volume":"14","author":"Cao","year":"2024","journal-title":"Cell Biosci."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1038\/s41598-017-00341-2","article-title":"Quantitative profiling of glycerophospholipids during mouse and human macrophage differentiation using targeted mass spectrometry","volume":"7","author":"Zhang","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Upadhyay, G. (2019). Emerging Role of Lymphocyte Antigen-6 Family of Genes in Cancer and Immune Cells. Front. Immunol., 10.","DOI":"10.3389\/fimmu.2019.00819"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1181","DOI":"10.1038\/ni1126","article-title":"Amplification of IFN-\u03b1-induced STAT1 activation and inflammatory function by Syk and ITAM-containing adaptors","volume":"5","author":"Tassiulas","year":"2004","journal-title":"Nat. Immunol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"761","DOI":"10.1038\/icb.2014.51","article-title":"STAT1 plays a role in TLR signal transduction and inflammatory responses","volume":"92","author":"Luu","year":"2014","journal-title":"Immunol. Cell Biol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"4880","DOI":"10.4049\/jimmunol.174.8.4880","article-title":"STAT1 signaling regulates tumor-associated macrophage-mediated T cell deletion","volume":"174","author":"Kusmartsev","year":"2005","journal-title":"J. Immunol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"6410","DOI":"10.1158\/0008-5472.CAN-11-1565","article-title":"IRF-1 expression is essential for natural killer cells to suppress metastasis","volume":"71","author":"Ksienzyk","year":"2011","journal-title":"Cancer Res."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"4187","DOI":"10.4049\/jimmunol.171.8.4187","article-title":"IFN-\u03b3-induced MHC class II expression: Transactivation of class II transactivator promoter IV by IFN regulatory factor-1 is regulated by protein kinase C-\u03b1","volume":"171","author":"Giroux","year":"2003","journal-title":"J. Immunol."},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Santinelli-Pestana, D.V., Aikawa, E., Singh, S.A., and Aikawa, M. (2023). PARPs and ADP-Ribosylation in Chronic Inflammation: A Focus on Macrophages. Pathogens, 12.","DOI":"10.3390\/pathogens12070964"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1459","DOI":"10.1194\/jlr.M020941","article-title":"Silencing of enzymes involved in ceramide biosynthesis causes distinct global alterations of lipid homeostasis and gene expression","volume":"53","author":"Ruangsiriluk","year":"2012","journal-title":"J. Lipid Res."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"440","DOI":"10.1111\/j.1478-3231.2007.01475.x","article-title":"Sphingolipid signalling and liver diseases","volume":"27","year":"2007","journal-title":"Liver Int."},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Jakobi, K., Beyer, S., Koch, A., Thomas, D., Schwalm, S., Zeuzem, S., Pfeilschifter, J., and Grammatikos, G. (2020). Sorafenib Treatment and Modulation of the Sphingolipid Pathway Affect Proliferation and Viability of Hepatocellular Carcinoma In Vitro. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21072409"},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Luthers, C.R., Dunn, T.M., and Snow, A.L. (2020). ORMDL3 and Asthma: Linking Sphingolipid Regulation to Altered T Cell Function. Front. Immunol., 11.","DOI":"10.3389\/fimmu.2020.597945"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"2533","DOI":"10.3748\/wjg.v22.i8.2533","article-title":"Dietary saturated fatty acid and polyunsaturated fatty acid oppositely affect hepatic NOD-like receptor protein 3 inflammasome through regulating nuclear factor-kappa B activation","volume":"22","author":"Sui","year":"2016","journal-title":"World J. Gastroenterol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"807","DOI":"10.1016\/j.it.2021.07.005","article-title":"Lipid regulation of NLRP3 inflammasome activity through organelle stress","volume":"42","author":"Liang","year":"2021","journal-title":"Trends Immunol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1038\/s41467-024-55785-8","article-title":"S100P is a ferroptosis suppressor to facilitate hepatocellular carcinoma development by rewiring lipid metabolism","volume":"16","author":"Yang","year":"2025","journal-title":"Nat. Commun."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1082","DOI":"10.7150\/ijbs.118753","article-title":"Combining sorafenib with spermine and sphingosine synergistically enhances anticancer efficacy by modulating metabolic pathways and gut microbiome in hepatocellular carcinoma","volume":"22","author":"Jang","year":"2026","journal-title":"Int. J. Biol. Sci."},{"key":"ref_66","unstructured":"(2026, April 28). Genome Sequence Archive. Available online: https:\/\/ngdc.cncb.ac.cn\/gsa\/search?searchTerm=CRA034182."},{"key":"ref_67","unstructured":"(2026, April 28). METASPACE. Available online: https:\/\/metaspace2020.org\/api_auth\/review?prj=e771287e-cff7-11f0-a049-7fb39272046b&token=VDPwuiObG3Gw."}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/16\/5\/675\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,4]],"date-time":"2026-05-04T02:32:25Z","timestamp":1777861945000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/16\/5\/675"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,2]]},"references-count":67,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2026,5]]}},"alternative-id":["biom16050675"],"URL":"https:\/\/doi.org\/10.3390\/biom16050675","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,2]]}}}