{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T11:28:48Z","timestamp":1786447728174,"version":"build-2736575974"},"reference-count":73,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2026,8,8]],"date-time":"2026-08-08T00:00:00Z","timestamp":1786147200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100012905","name":"Shandong Provincial Key Research and Development Plan","doi-asserted-by":"publisher","award":["2022LZGCQY016"],"award-info":[{"award-number":["2022LZGCQY016"]}],"id":[{"id":"10.13039\/100012905","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32472896"],"award-info":[{"award-number":["32472896"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"award":["32472896"],"award-info":[{"award-number":["32472896"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Jiangxi Provincial Joint Research Project","award":["2022JXCQZY05"],"award-info":[{"award-number":["2022JXCQZY05"]}]},{"name":"National Joint Breeding Research Project"},{"name":"2115 Talent Development Program of China Agricultural University"},{"id":[{"id":"https:\/\/ror.org\/04v3ywz14","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Heme oxygenase-1 (HO-1), encoded by HMOX1, catalyzes the rate-limiting step of heme degradation and generates biliverdin, carbon monoxide, and ferrous iron, thereby linking heme turnover with redox regulation and stress-associated signaling. In birds, biliverdin is retained as a major heme-derived product, but the cellular consequences of HMOX1 perturbation remain insufficiently defined. Here, CRISPR\/Cas9-mediated editing was used to generate a heterogeneous HMOX1-edited population in Chicken hepatocellular carcinoma-derived cells. The selected sgRNA reduced HO-1 protein abundance by approximately 47%, and no detectable cleavage was observed at the seven predicted high-risk off-target loci examined. Compared with vector-control cells, HMOX1-edited cells exhibited intracellular heme accumulation, reduced biliverdin levels, increased oxidation-sensitive fluorescence, and reduced CCK-8 absorbance values, indicating disruption of heme\u2013biliverdin metabolic and redox homeostasis. RNA sequencing identified 2650 differentially expressed genes, including 951 upregulated and 1699 downregulated genes. Downregulated genes were mainly enriched in immune, cytokine, MAPK\/stress, and extracellular signaling-associated pathways, whereas DNA replication and cell-cycle-related genes were increased. Enrichment-term association and STRING functional-association analyses further identified a coordinated module involving IL1B, JUN, NFKBIA, IRF1, TGFB1, IL10, CCL5, and PTGS2. Independent RT-qPCR analysis confirmed selected expression trends. These findings show that heterogeneous HMOX1 editing and reduced HO-1 abundance are associated with disruption of the avian heme\u2013biliverdin metabolic axis and coordinated remodeling of basal immune, stress, extracellular signaling, and cell-cycle-associated transcriptional programs in Chicken hepatocellular carcinoma-derived cells.<\/jats:p>","DOI":"10.3390\/ijms27167120","type":"journal-article","created":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T09:24:53Z","timestamp":1786353893000},"page":"7120","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Heterogeneous CRISPR\/Cas9 Editing of HMOX1 Is Associated with Altered Heme\u2013Biliverdin Metabolism and Basal Stress-Associated Transcriptional Programs in Chicken LMH Cells"],"prefix":"10.3390","volume":"27","author":[{"given":"Haonan","family":"Tang","sequence":"first","affiliation":[{"name":"Key Laboratory of Animal Genetics, Breeding and Reproduction, Ministry of Agriculture, Beijing Key Laboratory for Animal Genetic Improvement, State Key Laboratory of Animal Biotech Breeding, China Agricultural University, Beijing 100193, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huaiyu","family":"Li","sequence":"additional","affiliation":[{"name":"Key Laboratory of Animal Genetics, Breeding and Reproduction, Ministry of Agriculture, Beijing Key Laboratory for Animal Genetic Improvement, State Key Laboratory of Animal Biotech Breeding, China Agricultural University, Beijing 100193, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yurong","family":"Tai","sequence":"additional","affiliation":[{"name":"Key Laboratory of Animal Genetics, Breeding and Reproduction, Ministry of Agriculture, Beijing Key Laboratory for Animal Genetic Improvement, State Key Laboratory of Animal Biotech Breeding, China Agricultural University, Beijing 100193, China"},{"name":"Sanya Institute, China Agricultural University, Sanya 572025, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xue","family":"Yang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Animal Genetics, Breeding and Reproduction, Ministry of Agriculture, Beijing Key Laboratory for Animal Genetic Improvement, State Key Laboratory of Animal Biotech Breeding, China Agricultural University, Beijing 100193, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Letian","family":"Zhang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Animal Genetics, Breeding and Reproduction, Ministry of Agriculture, Beijing Key Laboratory for Animal Genetic Improvement, State Key Laboratory of Animal Biotech Breeding, China Agricultural University, Beijing 100193, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuhao","family":"Ma","sequence":"additional","affiliation":[{"name":"Key Laboratory of Animal Genetics, Breeding and Reproduction, Ministry of Agriculture, Beijing Key Laboratory for Animal Genetic Improvement, State Key Laboratory of Animal Biotech Breeding, China Agricultural University, Beijing 100193, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ganxian","family":"Cai","sequence":"additional","affiliation":[{"name":"Key Laboratory of Animal Genetics, Breeding and Reproduction, Ministry of Agriculture, Beijing Key Laboratory for Animal Genetic Improvement, State Key Laboratory of Animal Biotech Breeding, China Agricultural University, Beijing 100193, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongyang","family":"Zhao","sequence":"additional","affiliation":[{"name":"Key Laboratory of Animal Genetics, Breeding and Reproduction, Ministry of Agriculture, Beijing Key Laboratory for Animal Genetic Improvement, State Key Laboratory of Animal Biotech Breeding, China Agricultural University, Beijing 100193, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tong","family":"Zeng","sequence":"additional","affiliation":[{"name":"Key Laboratory of Animal Genetics, Breeding and Reproduction, Ministry of Agriculture, Beijing Key Laboratory for Animal Genetic Improvement, State Key Laboratory of Animal Biotech Breeding, China Agricultural University, Beijing 100193, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaohua","family":"Ai","sequence":"additional","affiliation":[{"name":"Key Laboratory of Animal Genetics, Breeding and Reproduction, Ministry of Agriculture, Beijing Key Laboratory for Animal Genetic Improvement, State Key Laboratory of Animal Biotech Breeding, China Agricultural University, Beijing 100193, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuang","family":"He","sequence":"additional","affiliation":[{"name":"Key Laboratory of Animal Genetics, Breeding and Reproduction, Ministry of Agriculture, Beijing Key Laboratory for Animal Genetic Improvement, State Key Laboratory of Animal Biotech Breeding, China Agricultural University, Beijing 100193, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiankui","family":"Wang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Animal Genetics, Breeding and Reproduction, Ministry of Agriculture, Beijing Key Laboratory for Animal Genetic Improvement, State Key Laboratory of Animal Biotech Breeding, China Agricultural University, Beijing 100193, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiliang","family":"Gu","sequence":"additional","affiliation":[{"name":"College of Biology and Food Engineering, Suzhou University of Technology, Suzhou 215500, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuemei","family":"Deng","sequence":"additional","affiliation":[{"name":"Key Laboratory of Animal Genetics, Breeding and Reproduction, Ministry of Agriculture, Beijing Key Laboratory for Animal Genetic Improvement, State Key Laboratory of Animal Biotech Breeding, China Agricultural University, Beijing 100193, China"},{"name":"Sanya Institute, China Agricultural University, Sanya 572025, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"6388","DOI":"10.1016\/S0021-9258(18)63477-5","article-title":"Microsomal Heme Oxygenase","volume":"244","author":"Tenhunen","year":"1969","journal-title":"J. Biol. Chem."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1089\/152308602760598891","article-title":"Heme Oxygenase-1: Redox Regulation and Role in the Hepatic Response to Oxidative Stress","volume":"4","author":"Bauer","year":"2002","journal-title":"Antioxid. Redox Signal"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1073\/pnas.86.1.99","article-title":"Heme Oxygenase Is the Major 32-kDa Stress Protein Induced in Human Skin Fibroblasts by UVA Radiation, Hydrogen Peroxide, and Sodium Arsenite","volume":"86","author":"Keyse","year":"1989","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"6371","DOI":"10.1016\/S0021-9258(18)83358-0","article-title":"Transcriptional Activation of the Heme Oxygenase Gene by Heme and Cadmium in Mouse Hepatoma Cells","volume":"264","author":"Alam","year":"1989","journal-title":"J. Biol. Chem."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"18411","DOI":"10.1074\/jbc.272.29.18411","article-title":"Thiol Compounds Interact with Nitric Oxide in Regulating Heme Oxygenase-1 Induction in Endothelial Cells","volume":"272","author":"Foresti","year":"1997","journal-title":"J. Biol. Chem."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1089\/ars.2005.7.80","article-title":"Heme Oxygenase-1: Redox Regulation of a Stress Protein in Lung and Cell Culture Models","volume":"7","author":"Ryter","year":"2005","journal-title":"Antioxid. Redox Signal."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"O\u2019Rourke, S.A., Shanley, L.C., and Dunne, A. (2024). The Nrf2-HO-1 System and Inflammaging. Front. Immunol., 15.","DOI":"10.3389\/fimmu.2024.1457010"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"863","DOI":"10.1016\/j.jare.2025.03.027","article-title":"Adaptive Bilirubin Nanoscavenger Alleviates Pulmonary Oxidative Stress and Inflammation for Acute Lung Injury Therapy","volume":"79","author":"Kou","year":"2025","journal-title":"J. Adv. Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1111\/j.1939-165X.1980.tb00887.x","article-title":"Hepatic Bile Pigment Excretion and Erythrocyte Turnover in Various Species","volume":"9","author":"Cornelius","year":"1980","journal-title":"Vet. Clin. Pathol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2547","DOI":"10.1161\/CIRCULATIONAHA.112.147082","article-title":"Bilirubin, the Gold Within","volume":"126","author":"Seppen","year":"2012","journal-title":"Circulation"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"836","DOI":"10.3382\/ps.2010-01143","article-title":"Expression and Activity Analysis Reveal That Heme Oxygenase (Decycling) 1 Is Associated with Blue Egg Formation","volume":"90","author":"Wang","year":"2011","journal-title":"Poult. Sci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1590\/S1415-47572013000200020","article-title":"Comparison of HMOX1 Expression and Enzyme Activity in Blue-Shelled Chickens and Brown-Shelled Chickens","volume":"36","author":"Wang","year":"2013","journal-title":"Genet. Mol. Biol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"100776","DOI":"10.1016\/j.animal.2023.100776","article-title":"The Pigments in Eggshell with Different Colour and the Pigment Regulatory Gene Expression in Corresponding Chicken\u2019s Shell Gland","volume":"17","author":"Wang","year":"2023","journal-title":"Animal"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1016\/S0378-1119(97)00623-9","article-title":"Molecular Cloning, Characterization, and Expression of the Chicken Heme Oxygenase-1 Gene in Transfected Primary Cultures of Chick Embryo Liver Cells","volume":"207","author":"Lu","year":"1998","journal-title":"Gene"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1023\/A:1007025505842","article-title":"Upstream Regulatory Elements in Chick Heme Oxygenase-1 Promoter: A Study in Primary Cultures of Chick Embryo Liver Cells","volume":"209","author":"Lu","year":"2000","journal-title":"Mol. Cell Biochem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"104990","DOI":"10.1016\/j.psj.2025.104990","article-title":"Dietary Selenium Mitigates Cadmium-Induced Apoptosis and Inflammation in Chicken Testicles by Inhibiting Oxidative Stress through the Activation of the Nrf2\/HO-1 Signaling Pathway","volume":"104","author":"Li","year":"2025","journal-title":"Poult. Sci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2016","DOI":"10.18632\/aging.101526","article-title":"Lycopene Ameliorates Oxidative Stress in the Aging Chicken Ovary via Activation of Nrf2\/HO-1 Pathway","volume":"10","author":"Liu","year":"2018","journal-title":"Aging"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Xie, L., Xu, Y., Ding, X., Li, K., Liang, S., Li, D., Wang, Y., Fu, A., Yu, W., and Zhan, X. (2023). Selenomethionine Attenuated H2O2-Induced Oxidative Stress and Apoptosis by Nrf2 in Chicken Liver Cells. Antioxidants, 12.","DOI":"10.3390\/antiox12091685"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1038\/s41577-020-00491-x","article-title":"Regulation of Inflammation by the Antioxidant Haem Oxygenase 1","volume":"21","author":"Campbell","year":"2021","journal-title":"Nat. Rev. Immunol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"e31465","DOI":"10.1002\/jcp.31465","article-title":"HO-1: An Emerging Target in Fibrosis","volume":"240","author":"Lu","year":"2025","journal-title":"J. Cell. Physiol."},{"key":"ref_21","first-page":"101038","article-title":"Clinical and Molecular Analysis of a Novel Variant in Heme Oxygenase-1 Deficiency: Unraveling Its Role in Inflammation, Heme Metabolism, and Pulmonary Phenotype","volume":"38","author":"Berendes","year":"2024","journal-title":"Mol. Genet. Metab. Rep."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1186\/s12944-023-01855-7","article-title":"Heme Oxygenase 1 Alleviates Nonalcoholic Steatohepatitis by Suppressing Hepatic Ferroptosis","volume":"22","author":"Yuan","year":"2023","journal-title":"Lipids Health Dis."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Mart\u00ednez, A., L\u00f3pez-Rull, I., and Fargallo, J.A. (2023). To Prevent Oxidative Stress, What about Protoporphyrin IX, Biliverdin, and Bilirubin?. Antioxidants, 12.","DOI":"10.3390\/antiox12091662"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1038\/s41418-017-0001-7","article-title":"Heme Accumulation in Endothelial Cells Impairs Angiogenesis by Triggering Paraptosis","volume":"25","author":"Petrillo","year":"2018","journal-title":"Cell Death Differ."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"787","DOI":"10.1038\/s41419-020-02950-8","article-title":"Heme Oxygenase 1 Protects Human Colonocytes against ROS Formation, Oxidative DNA Damage and Cytotoxicity Induced by Heme Iron, but Not Inorganic Iron","volume":"11","author":"Seiwert","year":"2020","journal-title":"Cell Death Dis."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"e65471","DOI":"10.7554\/eLife.65471","article-title":"DDK Regulates Replication Initiation by Controlling the Multiplicity of Cdc45-GINS Binding to Mcm2-7","volume":"10","author":"Friedman","year":"2021","journal-title":"eLife"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2612","DOI":"10.1128\/MCB.15.5.2612","article-title":"Human Cyclin E, a Nuclear Protein Essential for the G1-to-S Phase Transition","volume":"15","author":"Ohtsubo","year":"1995","journal-title":"Mol. Cell Biol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"11855","DOI":"10.1074\/jbc.M110.199521","article-title":"MCM2-7 Form Double Hexamers at Licensed Origins in Xenopus Egg Extract","volume":"286","author":"Gambus","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"414","DOI":"10.15252\/embr.201540984","article-title":"Feedback Regulation between Atypical E2Fs and APC\/CCdh1 Coordinates Cell Cycle Progression","volume":"17","author":"Boekhout","year":"2016","journal-title":"EMBO Rep."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"7155","DOI":"10.1073\/pnas.0811159106","article-title":"PALB2 Is an Integral Component of the BRCA Complex Required for Homologous Recombination Repair","volume":"106","author":"Sy","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1247","DOI":"10.1038\/nsmb.1915","article-title":"Cooperation of Breast Cancer Proteins PALB2 and Piccolo BRCA2 in Stimulating Homologous Recombination","volume":"17","author":"Buisson","year":"2010","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1016\/j.cell.2011.03.041","article-title":"Double-Strand Break Repair-Independent Role for BRCA2 in Blocking Stalled Replication Fork Degradation by MRE11","volume":"145","author":"Schlacher","year":"2011","journal-title":"Cell"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1016\/j.ccr.2012.05.015","article-title":"A Distinct Replication Fork Protection Pathway Connects Fanconi Anemia Tumor Suppressors to RAD51-BRCA1\/2","volume":"22","author":"Schlacher","year":"2012","journal-title":"Cancer Cell"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"5718","DOI":"10.1038\/s41467-019-13667-4","article-title":"ATAD5 Promotes Replication Restart by Regulating RAD51 and PCNA in Response to Replication Stress","volume":"10","author":"Park","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1083\/jcb.201406100","article-title":"DNA2 Drives Processing and Restart of Reversed Replication Forks in Human Cells","volume":"208","author":"Thangavel","year":"2015","journal-title":"J. Cell Biol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2558","DOI":"10.1016\/j.celrep.2019.05.002","article-title":"Human RIF1-Protein Phosphatase 1 Prevents Degradation and Breakage of Nascent DNA on Replication Stalling","volume":"27","author":"Ursich","year":"2019","journal-title":"Cell Rep."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1285","DOI":"10.1083\/jcb.201007074","article-title":"Chk1 Inhibits Replication Factory Activation but Allows Dormant Origin Firing in Existing Factories","volume":"191","author":"Ge","year":"2010","journal-title":"J. Cell Biol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"12855","DOI":"10.1074\/jbc.RA118.003740","article-title":"Uncoupling Fork Speed and Origin Activity to Identify the Primary Cause of Replicative Stress Phenotypes","volume":"293","year":"2018","journal-title":"J. Biol. Chem."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"103247","DOI":"10.1016\/j.redox.2024.103247","article-title":"Heme Oxygenase-1 Protects Cells from Replication Stress","volume":"75","author":"Chudy","year":"2024","journal-title":"Redox Biol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"927","DOI":"10.1038\/s41591-018-0049-z","article-title":"CRISPR-Cas9 Genome Editing Induces a P53-Mediated DNA Damage Response","volume":"24","author":"Haapaniemi","year":"2018","journal-title":"Nat. Med."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1016\/j.stem.2019.02.019","article-title":"Precise Gene Editing Preserves Hematopoietic Stem Cell Function Following Transient P53-Mediated DNA Damage Response","volume":"24","author":"Schiroli","year":"2019","journal-title":"Cell Stem Cell"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1535","DOI":"10.7150\/ijbs.25629","article-title":"Cellular Glucose Metabolism Is Essential for the Reduction of Cell-Impermeable Water-Soluble Tetrazolium (WST) Dyes","volume":"14","author":"Xie","year":"2018","journal-title":"Int. J. Biol. Sci."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Yachie, A. (2021). Heme Oxygenase-1 Deficiency and Oxidative Stress: A Review of 9 Independent Human Cases and Animal Models. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22041514"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1186\/s12950-025-00467-5","article-title":"Effect of Heme Oxygenase-1 on the Expression of Interferon-Stimulated Genes","volume":"22","author":"Chudy","year":"2025","journal-title":"J. Inflamm."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Kaszubowska, L., Kaczor, J.J., Karnia, M.J., Foerster, J., and Kmie\u0107, Z. (2024). Expression of a Stress-Inducible Heme Oxygenase-1 in NK Cells Is Maintained in the Process of Human Aging. Front. Immunol., 15.","DOI":"10.3389\/fimmu.2024.1398468"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"570","DOI":"10.1006\/bbrc.1996.0637","article-title":"The Heme-Responsive Element of the Mouse Heme Oxygenase-1 Gene Is an Extended AP-1 Binding Site That Resembles the Recognition Sequences for MAF and NF-E2 Transcription Factors","volume":"221","author":"Inamdar","year":"1996","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Aggeletopoulou, I., Kalafateli, M., Tsounis, E.P., and Triantos, C. (2024). Exploring the Role of IL-1\u03b2 in Inflammatory Bowel Disease Pathogenesis. Front. Med., 11.","DOI":"10.3389\/fmed.2024.1307394"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"147737","DOI":"10.1016\/j.ijbiomac.2025.147737","article-title":"C-C Motif Glycoprotein Ligand 5 (CCL5) and Its GPCR CCR5: Macromolecular Game-Changers in Cancer Biology","volume":"329","author":"Ghasemi","year":"2025","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"33","DOI":"10.18388\/pb.2021_521","article-title":"Self-Organisation of Early Stress Response in the Biology of Cancer","volume":"70","author":"Erenpreisa","year":"2024","journal-title":"Postep. Biochem."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Qing, F., and Liu, Z. (2023). Interferon Regulatory Factor 7 in Inflammation, Cancer and Infection. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1190841"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"105141","DOI":"10.1016\/j.critrevonc.2026.105141","article-title":"TGF-\u03b2-Mediated Suppression of NK Cell Function and Targeting Strategies in Tumor Immunotherapy","volume":"219","author":"Wang","year":"2026","journal-title":"Crit. Rev. Oncol.\/Hematol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1111\/cea.12697","article-title":"Cyclooxygenase 2: Its Regulation, Role and Impact in Airway Inflammation","volume":"46","author":"Rumzhum","year":"2016","journal-title":"Clin. Exp. Allergy"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1186\/s13567-018-0537-7","article-title":"A Chicken Liver Cell Line Efficiently Supports the Replication of ALV-J Possibly through Its High Level Viral Receptor and Efficient Protein Expression System","volume":"49","author":"Li","year":"2018","journal-title":"Vet. Res."},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Zhuang, W., Chen, Z., Shu, X., Zhang, J., Zhu, R., Shen, M., Chen, J., and Zheng, X. (2024). Establishment of a Steatosis Model in LMH Cells, Chicken Embryo Hepatocytes, and Liver Tissues Based on a Mixture of Sodium Oleate and Palmitic Acid. Animals, 14.","DOI":"10.3390\/ani14152173"},{"key":"ref_55","first-page":"4460","article-title":"Establishment and Characterization of a Chicken Hepatocellular Carcinoma Cell Line, LMH","volume":"47","author":"Kawaguchi","year":"1987","journal-title":"Cancer Res."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"2281","DOI":"10.1038\/nprot.2013.143","article-title":"Genome Engineering Using the CRISPR-Cas9 System","volume":"8","author":"Ran","year":"2013","journal-title":"Nat. Protoc."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1473","DOI":"10.1093\/bioinformatics\/btu048","article-title":"Cas-OFFinder: A Fast and Versatile Algorithm That Searches for Potential off-Target Sites of Cas9 RNA-Guided Endonucleases","volume":"30","author":"Bae","year":"2014","journal-title":"Bioinformatics"},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"The UniProt Consortium (2017). UniProt: The Universal Protein Knowledgebase. Nucleic Acids Res., 45, D158\u2013D169. Erratum in Nucleic Acids Res. 2018, 46, 2699.","DOI":"10.1093\/nar\/gkw1099"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1646","DOI":"10.1038\/s41598-017-01602-w","article-title":"Biliverdin Reductase Inhibitors Did Not Improve Severe Unconjugated Hyperbilirubinemia In Vivo","volume":"7","author":"Aronson","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"2114","DOI":"10.1093\/bioinformatics\/btu170","article-title":"Trimmomatic: A Flexible Trimmer for Illumina Sequence Data","volume":"30","author":"Bolger","year":"2014","journal-title":"Bioinformatics"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"907","DOI":"10.1038\/s41587-019-0201-4","article-title":"Graph-Based Genome Alignment and Genotyping with HISAT2 and HISAT-Genotype","volume":"37","author":"Kim","year":"2019","journal-title":"Nat. Biotechnol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"923","DOI":"10.1093\/bioinformatics\/btt656","article-title":"featureCounts: An Efficient General Purpose Program for Assigning Sequence Reads to Genomic Features","volume":"30","author":"Liao","year":"2014","journal-title":"Bioinformatics"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1093\/bioinformatics\/btp616","article-title":"edgeR: A Bioconductor Package for Differential Expression Analysis of Digital Gene Expression Data","volume":"26","author":"Robinson","year":"2010","journal-title":"Bioinformatics"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"W191","DOI":"10.1093\/nar\/gkz369","article-title":"G: Profiler: A Web Server for Functional Enrichment Analysis and Conversions of Gene Lists (2019 Update)","volume":"47","author":"Raudvere","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"15545","DOI":"10.1073\/pnas.0506580102","article-title":"Gene Set Enrichment Analysis: A Knowledge-Based Approach for Interpreting Genome-Wide Expression Profiles","volume":"102","author":"Subramanian","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1089\/omi.2011.0118","article-title":"clusterProfiler: An R Package for Comparing Biological Themes among Gene Clusters","volume":"16","author":"Yu","year":"2012","journal-title":"OMICS J. Integr. Biol."},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"Kong, R., Shi, J., Xie, K., Wu, H., Wang, X., Zhang, Y., and Wang, Y. (2024). A Study of JUN\u2019s Promoter Region and Its Regulators in Chickens. Genes, 15.","DOI":"10.3390\/genes15101351"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"102864","DOI":"10.1016\/j.psj.2023.102864","article-title":"Establishment and Characterization of an SV40 Immortalized Chicken Intestinal Epithelial Cell Line","volume":"102","author":"Ghiselli","year":"2023","journal-title":"Poult. Sci."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1292\/jvms.21-0410","article-title":"Characterization of Chicken IFI35 and Its Antiviral Activity against Newcastle Disease Virus","volume":"84","author":"Jia","year":"2022","journal-title":"J. Vet. Med. Sci."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"759","DOI":"10.17582\/journal.pjz\/20201110141107","article-title":"Identification of Nuclear Factor-\u03baB Pathway Genes in Chicken Erythrocytes and Their Expression Level in Erythrocytes after Infection with Mycoplasma Synoviae","volume":"56","author":"Khan","year":"2024","journal-title":"Pak. J. Zool."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1080\/00071668.2016.1237768","article-title":"Lipopolysaccharide Reduces Food Passage Rate from the Crop by a Prostaglandin-Independent Mechanism in Chickens","volume":"58","author":"Tachibana","year":"2017","journal-title":"Br. Poult. Sci."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"3041254","DOI":"10.1155\/vmi\/3041254","article-title":"Comparative Transcriptome Analysis of Hens\u2019 Livers in Conventional Cage vs. Cage-Free Egg Production Systems","volume":"2025","year":"2025","journal-title":"Vet. Med. Int."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"4598","DOI":"10.1016\/j.psj.2020.05.032","article-title":"The Effect of Total Flavonoids of Epimedium on Granulosa Cell Development in Laying Hens","volume":"99","author":"Guo","year":"2020","journal-title":"Poult. Sci."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/16\/7120\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T10:33:35Z","timestamp":1786444415000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/16\/7120"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,8]]},"references-count":73,"journal-issue":{"issue":"16","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["ijms27167120"],"URL":"https:\/\/doi.org\/10.3390\/ijms27167120","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,8]]}}}