{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T01:15:34Z","timestamp":1760058934744,"version":"build-2065373602"},"reference-count":52,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2025,5,8]],"date-time":"2025-05-08T00:00:00Z","timestamp":1746662400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Key Project of Taizhou Clinical College of Nanjing Medical University","award":["TZKY20230305","NMUB20240243"],"award-info":[{"award-number":["TZKY20230305","NMUB20240243"]}]},{"name":"Science and Technology Development Fund Project of Nanjing Medical University","award":["TZKY20230305","NMUB20240243"],"award-info":[{"award-number":["TZKY20230305","NMUB20240243"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biology"],"abstract":"<jats:p>Background: Metabolic dysfunction-associated steatotic liver disease (MASLD), a chronic inflammatory disorder characterized by alcohol-independent hepatic lipid accumulation, remains poorly understood in terms of PANoptosis involvement. Methods: We integrated high-throughput sequencing data with bioinformatics to profile differentially expressed genes (DEGs) and immune infiltration patterns in MASLD, identifying PANoptosis-associated DEGs (PANoDEGs). Machine learning algorithms prioritized key PANoDEGs, while ROC curves assessed their diagnostic efficacy. Cellular, animal, and clinical validations confirmed target expression. Results: Three PANoDEGs (SNHG16, Caspase-6, and Dynamin-1-like protein) exhibited strong MASLD associations and diagnostic significance. Immune profiling revealed elevated M1 macrophages, na\u00efve B cells, and activated natural killer cells in MASLD tissues versus controls. Further experiments verified the expression of the key PANoDEGs. Conclusions: This study provides new insights for further studies on the pathogenesis and treatment strategies of PANoptosis in MASLD.<\/jats:p>","DOI":"10.3390\/biology14050518","type":"journal-article","created":{"date-parts":[[2025,5,8]],"date-time":"2025-05-08T04:06:21Z","timestamp":1746677181000},"page":"518","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Comprehensive Analysis Reveals the Molecular Features and Immune Infiltration of PANoptosis-Related Genes in Metabolic Dysfunction-Associated Steatotic Liver Disease"],"prefix":"10.3390","volume":"14","author":[{"given":"Yan","family":"Huang","sequence":"first","affiliation":[{"name":"Medical College, Yangzhou University, Yangzhou 225000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jingyu","family":"Qian","sequence":"additional","affiliation":[{"name":"Taizhou School of Clinical Medicine, The Affiliated Taizhou People\u2019s Hospital of Nanjing Medical University, Taizhou 225300, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhengyun","family":"Luan","sequence":"additional","affiliation":[{"name":"Taizhou School of Clinical Medicine, The Affiliated Taizhou People\u2019s Hospital of Nanjing Medical University, Taizhou 225300, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Junling","family":"Han","sequence":"additional","affiliation":[{"name":"Taizhou School of Clinical Medicine, The Affiliated Taizhou People\u2019s Hospital of Nanjing Medical University, Taizhou 225300, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Limin","family":"Tang","sequence":"additional","affiliation":[{"name":"Taizhou School of Clinical Medicine, The Affiliated Taizhou People\u2019s Hospital of Nanjing Medical University, Taizhou 225300, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,5,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1388","DOI":"10.1002\/hep.28584","article-title":"Global epidemiology of nonalcoholic fatty liver disease: Meta-analytic assessment of prevalence, incidence, and outcomes","volume":"64","author":"Lonardo","year":"2016","journal-title":"Hepatology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2212","DOI":"10.1016\/S0140-6736(20)32511-3","article-title":"Non-alcoholic fatty liver disease","volume":"397","author":"Powell","year":"2021","journal-title":"Lancet"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e186424","DOI":"10.1172\/JCI186424","article-title":"Human genetics of metabolic dysfunction-associated steatotic liver disease: From variants to cause to precision treatment","volume":"135","author":"Chen","year":"2025","journal-title":"J. Clin. Investig."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1038\/s41572-025-00599-1","article-title":"Metabolic dysfunction-associated steatotic liver disease in adults","volume":"11","author":"Huang","year":"2025","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"773","DOI":"10.1016\/j.jhep.2017.11.040","article-title":"Gasdermin D plays a key role as a pyroptosis executor of non-alcoholic steatohepatitis in humans and mice","volume":"68","author":"Xu","year":"2018","journal-title":"J. Hepatol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"738","DOI":"10.1038\/s41575-018-0065-y","article-title":"Apoptosis and necroptosis in the liver: A matter of life and death","volume":"15","author":"Schwabe","year":"2018","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1761","DOI":"10.1111\/liv.15586","article-title":"Programmed cell death 1 genetic variant and liver damage in nonalcoholic fatty liver disease","volume":"43","author":"Pipitone","year":"2023","journal-title":"Liver Int."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"616","DOI":"10.1016\/j.jhep.2020.03.023","article-title":"MLKL-dependent signaling regulates autophagic flux in a murine model of non-alcohol-associated fatty liver and steatohepatitis","volume":"73","author":"Wu","year":"2020","journal-title":"J. Hepatol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1186\/s13046-024-03089-6","article-title":"Cell death shapes cancer immunity: Spotlighting PANoptosis","volume":"43","author":"Gao","year":"2024","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"739","DOI":"10.1016\/j.tips.2024.06.002","article-title":"PANoptosis: A novel target for cardiovascular diseases","volume":"45","author":"Xiang","year":"2024","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Malireddi, R.K.S., Kesavardhana, S., and Kanneganti, T.D. (2019). ZBP1 and TAK1: Master Regulators of NLRP3 Inflammasome\/Pyroptosis, Apoptosis, and Necroptosis (PAN-optosis). Front. Cell. Infect. Microbiol., 9.","DOI":"10.3389\/fcimb.2019.00406"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"4641","DOI":"10.1016\/j.csbj.2021.07.038","article-title":"From pyroptosis, apoptosis and necroptosis to PANoptosis: A mechanistic compendium of programmed cell death pathways","volume":"19","author":"Wang","year":"2021","journal-title":"Comput. Struct. Biotechnol. J."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1038\/s41586-021-03875-8","article-title":"AIM2 forms a complex with pyrin and ZBP1 to drive PANoptosis and host defence","volume":"597","author":"Lee","year":"2021","journal-title":"Nature"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"G1034","DOI":"10.1152\/ajpgi.00431.2020","article-title":"Mitochondrial DNA enables AIM2 inflammasome activation and hepatocyte pyroptosis in nonalcoholic fatty liver disease","volume":"320","author":"Xu","year":"2021","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1146\/annurev-pathmechdis-032521-102529","article-title":"Role of the Inflammasome in Liver Disease","volume":"17","author":"Szabo","year":"2022","journal-title":"Annu. Rev. Pathol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1016\/j.jcmgh.2022.06.007","article-title":"Cell-specific Deletion of NLRP3 Inflammasome Identifies Myeloid Cells as Key Drivers of Liver Inflammation and Fibrosis in Murine Steatohepatitis","volume":"14","author":"Kaufmann","year":"2022","journal-title":"Cell. Mol. Gastroenterol. Hepatol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2359","DOI":"10.1136\/gutjnl-2020-321767","article-title":"RIPK3 acts as a lipid metabolism regulator contributing to inflammation and carcinogenesis in non-alcoholic fatty liver disease","volume":"70","author":"Afonso","year":"2021","journal-title":"Gut"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1887","DOI":"10.1016\/j.dld.2024.05.010","article-title":"Identification of key markers for the stages of nonalcoholic fatty liver disease: An integrated bioinformatics analysis and experimental validation","volume":"56","author":"Muriel","year":"2024","journal-title":"Dig. Liver Dis."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"961","DOI":"10.1007\/s00011-024-01877-6","article-title":"Transcriptomic analysis reveals molecular characterization and immune landscape of PANoptosis-related genes in atherosclerosis","volume":"73","author":"Zheng","year":"2024","journal-title":"Inflamm. Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1016\/S2213-8587(18)30154-2","article-title":"Non-alcoholic fatty liver disease: Causes, diagnosis, cardiometabolic consequences, and treatment strategies","volume":"7","author":"Stefan","year":"2019","journal-title":"Lancet Diabetes Endocrinol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"20406223211048649","DOI":"10.1177\/20406223211048649","article-title":"The association between NAFLD and risk of chronic kidney disease: A cross-sectional study","volume":"12","author":"Cao","year":"2021","journal-title":"Ther. Adv. Chronic Dis."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"e076388","DOI":"10.1136\/bmj-2023-076388","article-title":"Association of non-alcoholic fatty liver disease with cardiovascular disease and all cause death in patients with type 2 diabetes mellitus: Nationwide population based study","volume":"384","author":"Kim","year":"2024","journal-title":"BMJ"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"235","DOI":"10.3350\/cmh.2023.0485","article-title":"Global incidence of adverse clinical events in non-alcoholic fatty liver disease: A systematic review and meta-analysis","volume":"30","author":"Le","year":"2024","journal-title":"Clin. Mol. Hepatol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"118057","DOI":"10.1016\/j.jep.2024.118057","article-title":"Si-Wu-Tang attenuates hepatocyte PANoptosis and M1 polarization of macrophages in non-alcoholic fatty liver disease by influencing the intercellular transfer of mtDNA","volume":"328","author":"Ma","year":"2024","journal-title":"J. Ethnopharmacol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"231","DOI":"10.7555\/JBR.36.20220049","article-title":"LncRNA SNHG16 promotes colorectal cancer proliferation by regulating ABCB1 expression through sponging miR-214-3p","volume":"36","author":"Tan","year":"2022","journal-title":"J. Biomed. Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1186\/s12935-020-01291-y","article-title":"SNHG16 promotes tumorigenesis and cisplatin resistance by regulating miR-338-3p\/PLK4 pathway in neuroblastoma cells","volume":"20","author":"Xu","year":"2020","journal-title":"Cancer Cell Int."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"e30388","DOI":"10.1016\/j.heliyon.2024.e30388","article-title":"Mechanism of lncRNA SNHG16 on kidney clear cell carcinoma cells by targeting miR-506-3p\/ETS1\/RAS\/ERK molecular axis","volume":"10","author":"Cheng","year":"2024","journal-title":"Heliyon"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Xiao, X., Jiang, G., Zhang, S., Hu, S., Fan, Y., Li, G., Yu, H., and He, S. (2021). LncRNA SNHG16 contributes to osteosarcoma progression by acting as a ceRNA of miR-1285-3p. BMC Cancer, 21.","DOI":"10.1186\/s12885-021-07933-2"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"11604","DOI":"10.1002\/jcb.28440","article-title":"LncRNA SNHG16 aggravates tumorigenesis and development of hepatocellular carcinoma by sponging miR-4500 and targeting STAT3","volume":"120","author":"Lin","year":"2019","journal-title":"J. Cell. Biochem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1090","DOI":"10.1002\/jcp.29023","article-title":"The lncRNA SNHG16 affects prognosis in hepatocellular carcinoma by regulating p62 expression","volume":"235","author":"Zhong","year":"2020","journal-title":"J. Cell. Physiol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"7637","DOI":"10.1111\/jcmm.15399","article-title":"SNHG16\/miR-605-3p\/TRAF6\/NF-\u03baB feedback loop regulates hepatocellular carcinoma metastasis","volume":"24","author":"Hu","year":"2020","journal-title":"J. Cell. Mol. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"4324","DOI":"10.1002\/cam4.3020","article-title":"SNGH16 regulates cell autophagy to promote Sorafenib Resistance through suppressing miR-23b-3p via sponging EGR1 in hepatocellular carcinoma","volume":"9","author":"Jing","year":"2020","journal-title":"Cancer Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"415","DOI":"10.2147\/OTT.S175176","article-title":"Long noncoding RNA SNHG16 induces sorafenib resistance in hepatocellular carcinoma cells through sponging miR-140-5p","volume":"12","author":"Ye","year":"2019","journal-title":"OncoTargets Ther."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1111\/imm.13633","article-title":"Caspase-6 is a key regulator of cross-talk signal way in PANoptosis in cancer","volume":"169","author":"Qi","year":"2023","journal-title":"Immunology"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"674","DOI":"10.1016\/j.cell.2020.03.040","article-title":"Caspase-6 Is a Key Regulator of Innate Immunity, Inflammasome Activation, and Host Defense","volume":"181","author":"Zheng","year":"2020","journal-title":"Cell"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Wang, L., Dong, W., Gao, H., Chen, C., Liang, S., Ye, X., Liu, Y., Hou, Y., Fan, L., and Pan, T. (2022). A non-mitogenic FGF4 analog alleviates non-alcoholic steatohepatitis through an AMPK-dependent pathway. Biochim. Et Biophys. Acta Mol. Basis Dis., 1868.","DOI":"10.1016\/j.bbadis.2022.166560"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"394","DOI":"10.1111\/bcpt.13535","article-title":"Salsalate reverses metabolic disorders in a mouse model of non-alcoholic fatty liver disease through AMPK activation and caspase-6 activity inhibition","volume":"128","author":"Li","year":"2021","journal-title":"Basic Clin. Pharmacol. Toxicol."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Zeng, Z., You, M., Fan, C., Rong, R., Li, H., and Xia, X. (2023). Pathologically high intraocular pressure induces mitochondrial dysfunction through Drp1 and leads to retinal ganglion cell PANoptosis in glaucoma. Redox Biol., 62.","DOI":"10.1016\/j.redox.2023.102687"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"101566","DOI":"10.1016\/j.molmet.2022.101566","article-title":"The mitochondrial fission protein Drp1 in liver is required to mitigate NASH and prevents the activation of the mitochondrial ISR","volume":"64","author":"Steffen","year":"2022","journal-title":"Mol. Metab."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"166831","DOI":"10.1016\/j.scitotenv.2023.166831","article-title":"Mystery of bisphenol F-induced nonalcoholic fatty liver disease-like changes: Roles of Drp1-mediated abnormal mitochondrial fission in lipid droplet deposition","volume":"904","author":"Zhang","year":"2023","journal-title":"Sci. Total Environ."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Zhong, Y., Li, Z., Jin, R., Yao, Y., He, S., Lei, M., Wang, X., Shi, C., Gao, L., and Peng, X. (2022). Diosgenin Ameliorated Type II Diabetes-Associated Nonalcoholic Fatty Liver Disease through Inhibiting De Novo Lipogenesis and Improving Fatty Acid Oxidation and Mitochondrial Function in Rats. Nutrients, 14.","DOI":"10.3390\/nu14234994"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1186\/s12944-023-01798-z","article-title":"Exercise activates Sirt1-mediated Drp1 acetylation and inhibits hepatocyte apoptosis to improve nonalcoholic fatty liver disease","volume":"22","author":"Hu","year":"2023","journal-title":"Lipids Health Dis."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1038\/s41577-021-00639-3","article-title":"Immune cell-mediated features of non-alcoholic steatohepatitis","volume":"22","author":"Huby","year":"2022","journal-title":"Nat. Rev. Immunol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1038\/s41575-018-0082-x","article-title":"The role of macrophages in nonalcoholic fatty liver disease and nonalcoholic steatohepatitis","volume":"16","author":"Kazankov","year":"2019","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"2537","DOI":"10.1016\/j.cell.2021.04.015","article-title":"Mechanisms and disease consequences of nonalcoholic fatty liver disease","volume":"184","author":"Loomba","year":"2021","journal-title":"Cell"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1038\/s41574-022-00675-6","article-title":"Macrophage functional diversity in NAFLD\u2014More than inflammation","volume":"18","author":"Barreby","year":"2022","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Li, Z., Wang, S., Xu, Q., Su, X., Wang, Y., Wang, L., and Zhang, Y. (2024). The double roles of T cell-mediated immune response in the progression of MASLD. Biomed. Pharmacother.=Biomed. Pharmacother., 173.","DOI":"10.1016\/j.biopha.2024.116333"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"e76","DOI":"10.1002\/imt2.76","article-title":"Decoding the role of immune T cells: A new territory for improvement of metabolic-associated fatty liver disease","volume":"2","author":"Liu","year":"2023","journal-title":"iMeta"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1038","DOI":"10.1002\/hep.32336","article-title":"T cells: Friends and foes in NASH pathogenesis and hepatocarcinogenesis","volume":"75","author":"Ramadori","year":"2022","journal-title":"Hepatology"},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Deng, C.J., Lo, T.H., Chan, K.Y., Li, X., Wu, M.Y., Xiang, Z., and Wong, C.M. (2022). Role of B Lymphocytes in the Pathogenesis of NAFLD: A 2022 Update. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms232012376"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"2277","DOI":"10.1002\/hep.31889","article-title":"The Emerging Role of B Cells in the Pathogenesis of NAFLD","volume":"74","author":"Barrow","year":"2021","journal-title":"Hepatology"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1002\/hep4.1146","article-title":"Insulin signaling as a potential natural killer cell checkpoint in fatty liver disease","volume":"2","author":"Amer","year":"2018","journal-title":"Hepatol. Commun."}],"container-title":["Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2079-7737\/14\/5\/518\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:29:06Z","timestamp":1760030946000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2079-7737\/14\/5\/518"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,8]]},"references-count":52,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2025,5]]}},"alternative-id":["biology14050518"],"URL":"https:\/\/doi.org\/10.3390\/biology14050518","relation":{},"ISSN":["2079-7737"],"issn-type":[{"type":"electronic","value":"2079-7737"}],"subject":[],"published":{"date-parts":[[2025,5,8]]}}}