{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T05:24:39Z","timestamp":1780637079334,"version":"3.54.1"},"reference-count":40,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,1,28]],"date-time":"2026-01-28T00:00:00Z","timestamp":1769558400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100012166","name":"National Key R&D Program of China","doi-asserted-by":"crossref","award":["2023YFD1801100"],"award-info":[{"award-number":["2023YFD1801100"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"crossref"}]},{"name":"\u201c2023 Young Leading Talents\u201d Project of Northeast Agricultural University","award":["NEAU2023QNLJ-012"],"award-info":[{"award-number":["NEAU2023QNLJ-012"]}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["32302947"],"award-info":[{"award-number":["32302947"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Animals"],"abstract":"<jats:p>Cadmium (Cd) is an environmental toxicant that poses significant risks to food safety and public health through its bioaccumulation in the food chain. The liver is a primary target for chronic Cd toxicity, yet the system-level mechanisms, particularly in physiologically relevant swine models, remain incompletely understood. This study employed an integrated multi-omics approach to elucidate the mechanisms of Cd-exposed hepatotoxicity in weaned piglets. We combined histopathological examination, transmission electron microscopy, and transcriptome sequencing. Our results revealed severe hepatic damage, characterized by disorganized architecture, vacuolar degeneration, mitochondrial dysfunction, and autophagic activation. Network toxicology predicted 3727 potential targets of Cd-exposed liver injury, while transcriptomics identified 1092 differentially expressed genes (DEGs). Crucially, the convergent analysis of both datasets demonstrated that the PI3K-Akt signaling pathway was the central hub, pinpointing it as a pivotal mechanism in Cd-driven hepatotoxicity. Functional enrichment analyses further highlighted dysregulation in immune-inflammatory responses, lipid metabolism, and oxidative stress. Our findings provide a comprehensive systems-level perspective on chronic Cd hepatotoxicity in a translational swine model. We propose the PI3K-Akt pathway and other identified core targets (EGFR, histones, ribosomal proteins) as critical biomarkers for monitoring Cd contamination in swine production chains, offering valuable insights for environmental risk assessment and agricultural product safety.<\/jats:p>","DOI":"10.3390\/ani16030414","type":"journal-article","created":{"date-parts":[[2026,1,28]],"date-time":"2026-01-28T15:56:12Z","timestamp":1769615772000},"page":"414","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Integrated Network Toxicology and Transcriptomics Reveal Molecular Mechanisms of Cadmium-Exposed Liver Injury in Swine"],"prefix":"10.3390","volume":"16","author":[{"given":"Nan","family":"Wang","sequence":"first","affiliation":[{"name":"College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuehan","family":"Jiang","sequence":"additional","affiliation":[{"name":"College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoxiao","family":"Chen","sequence":"additional","affiliation":[{"name":"College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Biner","family":"Zhao","sequence":"additional","affiliation":[{"name":"College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingzeng","family":"Cai","sequence":"additional","affiliation":[{"name":"College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, China"},{"name":"Key Laboratory of the Provincial Education, Department of Heilongjiang for Common Animal Disease Prevention and Treatment, Harbin 150038, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5705-4611","authenticated-orcid":false,"given":"Ziwei","family":"Zhang","sequence":"additional","affiliation":[{"name":"College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, China"},{"name":"Key Laboratory of the Provincial Education, Department of Heilongjiang for Common Animal Disease Prevention and Treatment, Harbin 150038, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Genchi, G., Sinicropi, M.S., Lauria, G., Carocci, A., and Catalano, A. (2020). The Effects of Cadmium Toxicity. Int. J. Environ. Res. Public Health, 17.","DOI":"10.3390\/ijerph17113782"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"106406","DOI":"10.1016\/j.envint.2021.106406","article-title":"Cadmium exposure impairs pancreatic beta-cell function and exaggerates diabetes by disrupting lipid metabolism","volume":"149","author":"Hong","year":"2021","journal-title":"Environ. Int."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1007\/s00134-011-2449-0","article-title":"Acute kidney injury following acute liver failure: Potential role of systemic cadmium mobilization?","volume":"38","author":"Hoet","year":"2012","journal-title":"Intensive Care Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1002\/(SICI)1099-0461(2000)14:2<110::AID-JBT7>3.0.CO;2-J","article-title":"Mechanisms of cadmium-mediated acute hepatotoxicity","volume":"14","author":"Rikans","year":"2000","journal-title":"J. Biochem. Mol. Toxicol."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Ma, Y., Su, Q., Yue, C., Zou, H., Zhu, J., Zhao, H., Song, R., and Liu, Z. (2022). The Effect of Oxidative Stress-Induced Autophagy by Cadmium Exposure in Kidney, Liver, and Bone Damage, and Neurotoxicity. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms232113491"},{"key":"ref_6","first-page":"151","article-title":"Comprehensive Review of Cadmium Toxicity Mechanisms in Male Reproduction and Therapeutic Strategies","volume":"258","author":"Xiong","year":"2021","journal-title":"Rev. Environ. Contam. Toxicol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"e22823","DOI":"10.1002\/jbt.22823","article-title":"Effects of heavy metals on reproduction owing to infertility","volume":"35","author":"Bhardwaj","year":"2021","journal-title":"J. Biochem. Mol. Toxicol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"112091","DOI":"10.1016\/j.ecoenv.2021.112091","article-title":"MAPK, AKT\/FoxO3a and mTOR pathways are involved in cadmium regulating the cell cycle, proliferation and apoptosis of chicken follicular granulosa cells","volume":"214","author":"Zhu","year":"2021","journal-title":"Ecotoxicol. Environ. Saf."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1080\/19393210.2011.589035","article-title":"Cadmium concentrations in the liver of 10 different pig genetic lines from Vojvodina, Serbia","volume":"4","author":"Tomovic","year":"2011","journal-title":"Food Addit. Contam. Part B"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Chalabis-Mazurek, A., Valverde Piedra, J.L., Muszynski, S., Tomaszewska, E., Szymanczyk, S., Kowalik, S., Arciszewski, M.B., Zacharko-Siembida, A., and Schwarz, T. (2021). The Concentration of Selected Heavy Metals in Muscles, Liver and Kidneys of Pigs Fed Standard Diets and Diets Containing 60% of New Rye Varieties. Animals, 11.","DOI":"10.3390\/ani11051377"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1007\/s10661-019-7274-x","article-title":"Micro- and macroelement contents in the liver of farm and wild animals and the health risks involved in liver consumption","volume":"191","author":"Kicinska","year":"2019","journal-title":"Environ. Monit. Assess."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Moroni-Gonzalez, D., Sarmiento-Ortega, V.E., Diaz, A., Brambila, E., and Trevino, S. (2023). Pancreas-Liver-Adipose Axis: Target of Environmental Cadmium Exposure Linked to Metabolic Diseases. Toxics, 11.","DOI":"10.3390\/toxics11030223"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2533","DOI":"10.1007\/s11033-021-06300-5","article-title":"The effect of N-Acetyl cysteine on the expression of Fxr (Nr1h4), LXRalpha (Nr1h3) and Sirt1 genes, oxidative stress, and apoptosis in the liver of rats exposed to different doses of cadmium","volume":"48","author":"Azarmehr","year":"2021","journal-title":"Mol. Biol. Rep."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1517\/17425255.2013.739607","article-title":"Animal models of toxicology testing: The role of pigs","volume":"9","author":"Helke","year":"2013","journal-title":"Expert Opin. Drug Metab. Toxicol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"105044","DOI":"10.1016\/j.rvsc.2023.105044","article-title":"The mechanism of cadmium exposure-induced lymph node necroptosis and inflammation in piglets: Activation of CYP450 through VDR\/CREB1 pathway","volume":"164","author":"Luo","year":"2023","journal-title":"Res. Vet. Sci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"113880","DOI":"10.1016\/j.ecoenv.2022.113880","article-title":"Cadmium exposure causes mitochondrial fission and fusion disorder in the pig hypothalamus via the PI3K\/AKT pathway","volume":"242","author":"Chen","year":"2022","journal-title":"Ecotoxicol. Environ. Saf."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"D325","DOI":"10.1093\/nar\/gkaa1113","article-title":"The Gene Ontology resource: Enriching a GOld mine","volume":"49","year":"2021","journal-title":"Nucleic Acids Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"W317","DOI":"10.1093\/nar\/gkab447","article-title":"KOBAS-i: Intelligent prioritization and exploratory visualization of biological functions for gene enrichment analysis","volume":"49","author":"Bu","year":"2021","journal-title":"Nucleic Acids Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1093\/bioinformatics\/btp612","article-title":"DEGseq: An R package for identifying differentially expressed genes from RNA-seq data","volume":"26","author":"Wang","year":"2010","journal-title":"Bioinformatics"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2805","DOI":"10.2147\/DDDT.S417954","article-title":"Deciphering the Mechanism of Xijiao Dihuang Decoction in Treating Psoriasis by Network Pharmacology and Experimental Validation","volume":"17","author":"Guo","year":"2023","journal-title":"Drug Des. Dev. Ther."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"126704","DOI":"10.1016\/j.jhazmat.2021.126704","article-title":"Cadmium exposure triggers oxidative stress, necroptosis, Th1\/Th2 imbalance and promotes inflammation through the TNF-alpha\/NF-kappaB pathway in swine small intestine","volume":"421","author":"Chen","year":"2022","journal-title":"J. Hazard. Mater."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"129735","DOI":"10.1016\/j.chemosphere.2021.129735","article-title":"Molecular mechanism of heavy metals (Lead, Chromium, Arsenic, Mercury, Nickel and Cadmium)-induced hepatotoxicity\u2014A review","volume":"271","author":"Renu","year":"2021","journal-title":"Chemosphere"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"120622","DOI":"10.1016\/j.lfs.2022.120622","article-title":"Melatonin relieves liver fibrosis induced by Txnrd3 knockdown and nickel exposure via IRE1\/NF-kB\/NLRP3 and PERK\/TGF-beta1 axis activation","volume":"301","author":"Liu","year":"2022","journal-title":"Life Sci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1016\/j.fsi.2022.05.021","article-title":"Astilbin attenuates apoptosis induced by cadmium through oxidative stress in carp (Cyprinus carpio L.) head kidney lymphocyte","volume":"125","author":"Zhang","year":"2022","journal-title":"Fish Shellfish Immunol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"114123","DOI":"10.1016\/j.ecoenv.2022.114123","article-title":"Cadmium induces liver dysfunction and ferroptosis through the endoplasmic stress-ferritinophagy axis","volume":"245","author":"He","year":"2022","journal-title":"Ecotoxicol. Environ. Saf."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"134684","DOI":"10.1016\/j.jhazmat.2024.134684","article-title":"Co-exposure of decabromodiphenyl ethane and cadmium increases toxicity to earthworms: Enrichment, oxidative stress, damage and molecular binding mechanisms","volume":"473","author":"Qiao","year":"2024","journal-title":"J. Hazard. Mater."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1007\/s40572-024-00463-6","article-title":"Mechanisms of Metal-Induced Hepatic Inflammation","volume":"11","author":"Subramaniam","year":"2024","journal-title":"Curr. Environ. Health Rep."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"152694","DOI":"10.1016\/j.tox.2021.152694","article-title":"Cadmium induces apoptosis of pig lymph nodes by regulating the PI3K\/AKT\/HIF-1alpha pathway","volume":"451","author":"Yiming","year":"2021","journal-title":"Toxicology"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1007\/s00204-024-03903-2","article-title":"Heavy metals: Toxicity and human health effects","volume":"99","author":"Jomova","year":"2025","journal-title":"Arch. Toxicol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1160","DOI":"10.1161\/CIRCRESAHA.123.323617","article-title":"Heavy Metal Exposure and Cardiovascular Disease","volume":"134","author":"Pan","year":"2024","journal-title":"Circ. Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"4075","DOI":"10.1002\/ptr.7071","article-title":"A review on the protective effects of naringenin against natural and chemical toxic agents","volume":"35","author":"Naraki","year":"2021","journal-title":"Phytother. Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"100790","DOI":"10.1016\/j.drup.2021.100790","article-title":"Why may citrate sodium significantly increase the effectiveness of transarterial chemoembolization in hepatocellular carcinoma?","volume":"59","author":"Icard","year":"2021","journal-title":"Drug Resist. Updat."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Stavrou, A., Ortiz, A., and Costa, M. (2023). Cadmium Activates EGFR\/STAT5 Signaling to Overcome Calcium Chelation and Promote Epithelial to Mesenchymal Transition. Biomolecules, 13.","DOI":"10.3390\/biom13010116"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"165699","DOI":"10.1016\/j.scitotenv.2023.165699","article-title":"Cadmium promotes colorectal cancer metastasis through EGFR\/Akt\/mTOR signaling cascade and dynamics","volume":"899","author":"Sun","year":"2023","journal-title":"Sci. Total Environ."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"3075","DOI":"10.1158\/0008-5472.CAN-17-3024","article-title":"Cotargeting BCL-2 and PI3K Induces BAX-Dependent Mitochondrial Apoptosis in AML Cells","volume":"78","author":"Rahmani","year":"2018","journal-title":"Cancer Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"112058","DOI":"10.1016\/j.ecoenv.2021.112058","article-title":"Cadmium exposure induces rat proximal tubular cells injury via p62-dependent Nrf2 nucleus translocation mediated activation of AMPK\/AKT\/mTOR pathway","volume":"214","author":"Dong","year":"2021","journal-title":"Ecotoxicol. Environ. Saf."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"41207","DOI":"10.1007\/s11356-022-18863-2","article-title":"Cadmium induces apoptosis and autophagy in swine small intestine by downregulating the PI3K\/Akt pathway","volume":"29","author":"Zhang","year":"2022","journal-title":"Environ. Sci. Pollut. Res. Int."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"31189","DOI":"10.1073\/pnas.2017152117","article-title":"Oncogenic activation of PI3K-AKT-mTOR signaling suppresses ferroptosis via SREBP-mediated lipogenesis","volume":"117","author":"Yi","year":"2020","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1007\/s10555-023-10156-5","article-title":"Regulation and targeting of SREBP-1 in hepatocellular carcinoma","volume":"43","author":"Su","year":"2024","journal-title":"Cancer Metastasis Rev."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"113015","DOI":"10.1016\/j.ecoenv.2021.113015","article-title":"Cadmium exposure activates the PI3K\/AKT signaling pathway through miRNA-21, induces an increase in M1 polarization of macrophages, and leads to fibrosis of pig liver tissue","volume":"228","author":"Cui","year":"2021","journal-title":"Ecotoxicol. Environ. 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