{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T00:25:36Z","timestamp":1792801536447,"version":"4.5.0"},"reference-count":75,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,2,13]],"date-time":"2026-02-13T00:00:00Z","timestamp":1770940800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,2,13]],"date-time":"2026-02-13T00:00:00Z","timestamp":1770940800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"the National Key R&D Program of China","award":["2022YFD130040307"],"award-info":[{"award-number":["2022YFD130040307"]}]},{"name":"the Jiangsu Agricultural Science and Technology Innovation Fund","award":["CX(24)1012"],"award-info":[{"award-number":["CX(24)1012"]}],"id":[{"id":"https:\/\/ror.org\/0335n2618","id-type":"ROR","asserted-by":"crossref"}]},{"name":"the Fundamental Research Funds for the Central Universities","award":["KYCXJC2024001"],"award-info":[{"award-number":["KYCXJC2024001"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J Animal Sci Biotechnol"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Iron deficiency (ID) poses a significant health burden to both human infants and suckling piglets. In piglets, ID leads to substantial economic losses for the industry by compromising growth performance, health, and survival. However, current research has predominantly concentrated on hematological abnormalities, whereas the mechanisms underlying ID-associated hepatic inflammatory injury remain inadequately elucidated. Our study employed the iron-deficient suckling piglet model to address this knowledge gap and to establish a molecular theoretical foundation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      To investigate the underlying mechanisms, this study conducted in vivo and in vitro models. In piglets, ID triggered hepatic oxidative stress by inducing a redox imbalance and suppressing the core Nrf2\/HO-1 antioxidant signaling pathway. Histopathological examination revealed structural abnormalities in ID piglet livers, including disorganized hepatic cords, cytoplasmic vacuolation, hydropic degeneration, and mononuclear inflammatory cell infiltration. Transmission electron microscopy further showed shrunk nuclear envelopes, reduced numbers of rough endoplasmic reticulum (RER), and dilated RER cisternae in hepatocytes of ID piglets. Mechanistically, ID activated endoplasmic reticulum stress (ERS) and the PERK\/IRE1\u03b1 branches of the unfolded protein response (UPR). RNA-seq transcriptomic analysis demonstrated significant dysregulation of immune-related pathways, accompanied by elevated pro-inflammatory cytokines (e.g.,\n                      <jats:italic>IL1B<\/jats:italic>\n                      ,\n                      <jats:italic>TNF<\/jats:italic>\n                      ) and decreased anti-inflammatory cytokines (e.g.,\n                      <jats:italic>IL4<\/jats:italic>\n                      ,\n                      <jats:italic>IL10<\/jats:italic>\n                      ). Central to this inflammatory response was the activation of the TLR4\/NF-\u03baB pathway, evidenced by upregulation of MyD88 and increased phosphorylation of I\u03baB\u03b1 and NF-\u03baB p65. In vitro, deferoxamine (DFO)-induced ID in AML12 hepatocytes consistently recapitulated the key features of this phenotype, including the activation of ERS\/ UPR and the TLR4\/NF-\u03baB signaling pathway. Pharmacological inhibition of ERS by 4-phenylbutyric acid (4-PBA) attenuated DFO-induced NF-\u03baB activation and ameliorated the imbalance between pro- and anti-inflammatory cytokines.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>ID exacerbated hepatic inflammation through ERS-mediated activation of the NF-\u03baB pathway, providing novel mechanistic insights into liver injury associated with ID.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Graphical Abstract<\/jats:title>\n                  <\/jats:sec>","DOI":"10.1186\/s40104-026-01356-4","type":"journal-article","created":{"date-parts":[[2026,2,13]],"date-time":"2026-02-13T00:03:37Z","timestamp":1770941017000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Iron deficiency aggravates hepatic inflammation in suckling piglets via endoplasmic reticulum stress-driven NF-\u03baB pathway activation"],"prefix":"10.1186","volume":"17","author":[{"given":"Jun","family":"Qi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaxu","family":"Liang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongming","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weite","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fei","family":"Long","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meng","family":"Yuan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhangbo","family":"Lou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunxue","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gaiqin","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bencheng","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiang","family":"Zhong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,2,13]]},"reference":[{"issue":"9","key":"1356_CR1","doi-asserted-by":"publisher","first-page":"1994","DOI":"10.1007\/s11427-022-2339-0","volume":"66","author":"S Jin","year":"2023","unstructured":"Jin S, He L, Yang C, He X, Chen H, Feng Y, et al. Crosstalk between trace elements and T-cell immunity during early-life health in pigs. Sci China Life Sci. 2023;66(9):1994\u20132005. https:\/\/doi.org\/10.1007\/s11427-022-2339-0.","journal-title":"Sci China Life Sci"},{"issue":"2","key":"1356_CR2","doi-asserted-by":"publisher","first-page":"199","DOI":"10.1016\/j.taap.2004.06.021","volume":"202","author":"G Papanikolaou","year":"2005","unstructured":"Papanikolaou G, Pantopoulos K. Iron metabolism and toxicity. Toxicol Appl Pharmacol. 2005;202(2):199\u2013211. https:\/\/doi.org\/10.1016\/j.taap.2004.06.021.","journal-title":"Toxicol Appl Pharmacol"},{"issue":"12","key":"1356_CR3","doi-asserted-by":"publisher","first-page":"4068","DOI":"10.2527\/jas.2010-3736","volume":"89","author":"JS Jolliff","year":"2011","unstructured":"Jolliff JS, Mahan DC. Effect of injected and dietary iron in young pigs on blood hematology and postnatal pig growth performance. J Anim Sci. 2011;89(12):4068\u201380. https:\/\/doi.org\/10.2527\/jas.2010-3736.","journal-title":"J Anim Sci"},{"issue":"4","key":"1356_CR4","doi-asserted-by":"publisher","first-page":"314","DOI":"10.1016\/s0368-1742(47)80037-2","volume":"57","author":"JA Venn","year":"1947","unstructured":"Venn JA, McCance RA, Widdowson EM. Iron metabolism in piglet anaemia. J Comp Pathol Ther. 1947;57(4):314\u201325. https:\/\/doi.org\/10.1016\/s0368-1742(47)80037-2.","journal-title":"J Comp Pathol Ther"},{"issue":"9","key":"1356_CR5","doi-asserted-by":"publisher","first-page":"2086","DOI":"10.1007\/s11427-022-2409-0","volume":"66","author":"Z Dong","year":"2023","unstructured":"Dong Z, Liu S, Deng Q, Li G, Tang Y, Wu X, et al. Role of iron in host-microbiota interaction and its effects on intestinal mucosal growth and immune plasticity in a piglet model. Sci China Life Sci. 2023;66(9):2086\u201398. https:\/\/doi.org\/10.1007\/s11427-022-2409-0.","journal-title":"Sci China Life Sci"},{"issue":"4","key":"1356_CR6","doi-asserted-by":"publisher","first-page":"420","DOI":"10.1055\/s-2005-923314","volume":"25","author":"GJ Anderson","year":"2005","unstructured":"Anderson GJ, Frazer DM. Hepatic iron metabolism. Semin Liver Dis. 2005;25(4):420\u201332. https:\/\/doi.org\/10.1055\/s-2005-923314.","journal-title":"Semin Liver Dis"},{"issue":"1","key":"1356_CR7","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1038\/cr.2009.139","volume":"20","author":"JR Dunkelberger","year":"2010","unstructured":"Dunkelberger JR, Song WC. Complement and its role in innate and adaptive immune responses. Cell Res. 2010;20(1):34\u201350. https:\/\/doi.org\/10.1038\/cr.2009.139.","journal-title":"Cell Res"},{"issue":"8","key":"1356_CR8","doi-asserted-by":"publisher","first-page":"1499","DOI":"10.3945\/jn.116.231621","volume":"146","author":"Y Li","year":"2016","unstructured":"Li Y, Hansen SL, Borst LB, Spears JW, Moeser AJ. Dietary iron deficiency and oversupplementation increase intestinal permeability, ion transport, and inflammation in pigs. J Nutr. 2016;146(8):1499\u2013505. https:\/\/doi.org\/10.3945\/jn.116.231621.","journal-title":"J Nutr"},{"issue":"7","key":"1356_CR9","doi-asserted-by":"publisher","first-page":"2028","DOI":"10.1093\/jn\/131.7.2028","volume":"131","author":"SR Kuvibidila","year":"2001","unstructured":"Kuvibidila SR, Porretta C, Baliga BS. Iron deficiency alters the progression of mitogen-treated murine splenic lymphocytes through the cell cycle. J Nutr. 2001;131(7):2028\u201333. https:\/\/doi.org\/10.1093\/jn\/131.7.2028.","journal-title":"J Nutr"},{"issue":"40","key":"1356_CR10","doi-asserted-by":"publisher","first-page":"eabq4469","DOI":"10.1126\/sciadv.abq4469","volume":"8","author":"M Bonadonna","year":"2022","unstructured":"Bonadonna M, Altamura S, Tybl E, Palais G, Qatato M, Polycarpou-Schwarz M, et al. Iron regulatory protein (IRP)-mediated iron homeostasis is critical for neutrophil development and differentiation in the bone marrow. Sci Adv. 2022;8(40):eabq4469. https:\/\/doi.org\/10.1126\/sciadv.abq4469.","journal-title":"Sci Adv"},{"issue":"1","key":"1356_CR11","doi-asserted-by":"publisher","first-page":"50","DOI":"10.1111\/jipb.12297","volume":"57","author":"C Hawes","year":"2015","unstructured":"Hawes C, Kiviniemi P, Kriechbaumer V. The endoplasmic reticulum: a dynamic and well-connected organelle. J Integr Plant Biol. 2015;57(1):50\u201362. https:\/\/doi.org\/10.1111\/jipb.12297.","journal-title":"J Integr Plant Biol"},{"key":"1356_CR12","doi-asserted-by":"publisher","first-page":"1123769","DOI":"10.3389\/fendo.2023.1123769","volume":"14","author":"H Luo","year":"2023","unstructured":"Luo H, Jiao Q, Shen C, Shao C, Xie J, Chen Y, et al. Unraveling the roles of endoplasmic reticulum-associated degradation in metabolic disorders. Front Endocrinol (Lausanne). 2023;14:1123769. https:\/\/doi.org\/10.3389\/fendo.2023.1123769.","journal-title":"Front Endocrinol (Lausanne)"},{"issue":"1","key":"1356_CR13","doi-asserted-by":"publisher","first-page":"434","DOI":"10.3390\/ijms14010434","volume":"14","author":"B Bhandary","year":"2012","unstructured":"Bhandary B, Marahatta A, Kim HR, Chae HJ. An involvement of oxidative stress in endoplasmic reticulum stress and its associated diseases. Int J Mol Sci. 2012;14(1):434\u201356. https:\/\/doi.org\/10.3390\/ijms14010434.","journal-title":"Int J Mol Sci"},{"issue":"1","key":"1356_CR14","doi-asserted-by":"publisher","first-page":"185","DOI":"10.3390\/ijms24010185","volume":"24","author":"V Vestuto","year":"2022","unstructured":"Vestuto V, Di Sarno V, Musella S, Di Dona G, Moltedo O, Gomez-Monterrey IM, et al. New frontiers on ER stress modulation: are TRP channels the leading actors? Int J Mol Sci. 2022;24(1):185. https:\/\/doi.org\/10.3390\/ijms24010185.","journal-title":"Int J Mol Sci"},{"issue":"5695","key":"1356_CR15","doi-asserted-by":"publisher","first-page":"457","DOI":"10.1126\/science.1103160","volume":"306","author":"U Ozcan","year":"2004","unstructured":"Ozcan U, Cao Q, Yilmaz E, Lee AH, Iwakoshi NN, Ozdelen E, et al. Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science. 2004;306(5695):457\u201361. https:\/\/doi.org\/10.1126\/science.1103160.","journal-title":"Science"},{"issue":"8","key":"1356_CR16","doi-asserted-by":"publisher","first-page":"421","DOI":"10.1038\/s41580-020-0250-z","volume":"21","author":"C Hetz","year":"2020","unstructured":"Hetz C, Zhang K, Kaufman RJ. Mechanisms, regulation and functions of the unfolded protein response. Nat Rev Mol Cell Biol. 2020;21(8):421\u201338. https:\/\/doi.org\/10.1038\/s41580-020-0250-z.","journal-title":"Nat Rev Mol Cell Biol"},{"key":"1356_CR17","doi-asserted-by":"publisher","first-page":"102407","DOI":"10.1016\/j.redox.2022.102407","volume":"55","author":"Y Wang","year":"2022","unstructured":"Wang Y, Wang M, Liu Y, Tao H, Banerjee S, Srinivasan S, et al. Integrated regulation of stress responses, autophagy and survival by altered intracellular iron stores. Redox Biol. 2022;55:102407. https:\/\/doi.org\/10.1016\/j.redox.2022.102407.","journal-title":"Redox Biol"},{"issue":"5","key":"1356_CR18","doi-asserted-by":"publisher","first-page":"910","DOI":"10.1002\/ejhf.1154","volume":"20","author":"MF Hoes","year":"2018","unstructured":"Hoes MF, Grote Beverborg N, Kijlstra JD, Kuipers J, Swinkels DW, Giepmans BNG, et al. Iron deficiency impairs contractility of human cardiomyocytes through decreased mitochondrial function. Eur J Heart Fail. 2018;20(5):910\u20139. https:\/\/doi.org\/10.1002\/ejhf.1154.","journal-title":"Eur J Heart Fail"},{"key":"1356_CR19","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1016\/j.neuro.2013.06.002","volume":"38","author":"YA Seo","year":"2013","unstructured":"Seo YA, Li Y, Wessling-Resnick M. Iron depletion increases manganese uptake and potentiates apoptosis through ER stress. Neurotoxicology. 2013;38:67\u201373. https:\/\/doi.org\/10.1016\/j.neuro.2013.06.002.","journal-title":"Neurotoxicology"},{"issue":"11","key":"1356_CR20","doi-asserted-by":"publisher","first-page":"2050","DOI":"10.3945\/jn.112.165522","volume":"142","author":"JL Rytych","year":"2012","unstructured":"Rytych JL, Elmore MR, Burton MD, Conrad MS, Donovan SM, Dilger RN, et al. Early life iron deficiency impairs spatial cognition in neonatal piglets. J Nutr. 2012;142(11):2050\u20136. https:\/\/doi.org\/10.3945\/jn.112.165522.","journal-title":"J Nutr"},{"issue":"2","key":"1356_CR21","doi-asserted-by":"publisher","first-page":"120","DOI":"10.1080\/10590500902885684","volume":"27","author":"A Valavanidis","year":"2009","unstructured":"Valavanidis A, Vlachogianni T, Fiotakis C. 8-hydroxy-2\u2019 -deoxyguanosine (8-OHdG): a critical biomarker of oxidative stress and carcinogenesis. J Environ Sci Health C Environ Carcinog Ecotoxicol Rev. 2009;27(2):120\u201339. https:\/\/doi.org\/10.1080\/10590500902885684.","journal-title":"J Environ Sci Health C Environ Carcinog Ecotoxicol Rev"},{"issue":"1","key":"1356_CR22","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1016\/j.tjnut.2023.11.007","volume":"154","author":"TR Monko","year":"2024","unstructured":"Monko TR, Tripp EH, Burr SE, Gunderson KN, Lanier LM, Georgieff MK, et al. Cellular iron deficiency disrupts thyroid hormone regulated gene expression in developing hippocampal neurons. J Nutr. 2024;154(1):49\u201359. https:\/\/doi.org\/10.1016\/j.tjnut.2023.11.007.","journal-title":"J Nutr"},{"key":"1356_CR23","doi-asserted-by":"publisher","first-page":"102413","DOI":"10.1016\/j.redox.2022.102413","volume":"55","author":"H Zhou","year":"2022","unstructured":"Zhou H, Zhou YL, Mao JA, Tang LF, Xu J, Wang ZX, et al. NCOA4-mediated ferritinophagy is involved in ionizing radiation-induced ferroptosis of intestinal epithelial cells. Redox Biol. 2022;55:102413. https:\/\/doi.org\/10.1016\/j.redox.2022.102413.","journal-title":"Redox Biol"},{"key":"1356_CR24","doi-asserted-by":"publisher","first-page":"758","DOI":"10.1111\/j.1749-6632.1965.tb54077.x","volume":"119","author":"H Keberle","year":"1964","unstructured":"Keberle H. The biochemistry of desferrioxamine and its relation to iron metabolism. Ann N Y Acad Sci. 1964;119:758\u201368. https:\/\/doi.org\/10.1111\/j.1749-6632.1965.tb54077.x.","journal-title":"Ann N Y Acad Sci"},{"key":"1356_CR25","doi-asserted-by":"publisher","unstructured":"Wang L, Zhang D, Jiang B, Ding H, Feng S, Zhao C, et al. 4-Phenylbutyric acid attenuates soybean glycinin\/\u03b2-conglycinin-induced IPEC-J2 cells apoptosis by regulating the mitochondria-associated endoplasmic reticulum membrane and NLRP-3. J Agric Food Chem. 2024;72(11):5926\u201334. https:\/\/doi.org\/10.1021\/acs.jafc.3c09630.","DOI":"10.1021\/acs.jafc.3c09630"},{"key":"1356_CR26","doi-asserted-by":"publisher","unstructured":"Perri AM, Friendship RM, Harding JC, O\u2019Sullivan TL. An investigation of iron deficiency and anemia in piglets and the effect of iron status at weaning on post-weaning performance. J Swine Health Product. 2016;24(1):10\u201320. https:\/\/doi.org\/10.54846\/jshap\/922.","DOI":"10.54846\/jshap\/922"},{"issue":"5","key":"1356_CR27","doi-asserted-by":"publisher","first-page":"632","DOI":"10.3390\/nu10050632","volume":"10","author":"LC Knight","year":"2018","unstructured":"Knight LC, Dilger RN. Longitudinal effects of iron deficiency anemia and subsequent repletion on blood parameters and the rate and composition of growth in pigs. Nutrients. 2018;10(5):632. https:\/\/doi.org\/10.3390\/nu10050632.","journal-title":"Nutrients"},{"key":"1356_CR28","doi-asserted-by":"publisher","first-page":"109479","DOI":"10.1016\/j.biopha.2019.109479","volume":"120","author":"X Chen","year":"2019","unstructured":"Chen X, Zhang X, Zhao J, Tang X, Wang F, Du H. Split iron supplementation is beneficial for newborn piglets. Biomed Pharmacother. 2019;120:109479. https:\/\/doi.org\/10.1016\/j.biopha.2019.109479.","journal-title":"Biomed Pharmacother"},{"issue":"12","key":"1356_CR29","doi-asserted-by":"publisher","first-page":"1027","DOI":"10.3109\/10715762.2013.848277","volume":"47","author":"J Yin","year":"2013","unstructured":"Yin J, Ren W, Liu G, Duan J, Yang G, Wu L, et al. Birth oxidative stress and the development of an antioxidant system in newborn piglets. Free Radic Res. 2013;47(12):1027\u201335. https:\/\/doi.org\/10.3109\/10715762.2013.848277.","journal-title":"Free Radic Res"},{"issue":"4","key":"1356_CR30","doi-asserted-by":"publisher","first-page":"446","DOI":"10.3390\/antiox13040446","volume":"13","author":"A Meloni","year":"2024","unstructured":"Meloni A, Pistoia L, Spasiano A, Cossu A, Casini T, Massa A, et al. Oxidative stress and antioxidant status in adult patients with transfusion-dependent thalassemia: correlation with demographic, laboratory, and clinical biomarkers. Antioxidants. 2024;13(4):446. https:\/\/doi.org\/10.3390\/antiox13040446.","journal-title":"Antioxidants"},{"key":"1356_CR31","doi-asserted-by":"publisher","first-page":"e06","DOI":"10.15420\/cfr.2021.26","volume":"8","author":"P Martens","year":"2022","unstructured":"Martens P. The effect of iron deficiency on cardiac function and structure in heart failure with reduced rjection fraction. Card Fail Rev. 2022;8:e06. https:\/\/doi.org\/10.15420\/cfr.2021.26.","journal-title":"Card Fail Rev"},{"issue":"2","key":"1356_CR32","doi-asserted-by":"publisher","first-page":"208","DOI":"10.3390\/antiox13020208","volume":"13","author":"S Gensluckner","year":"2024","unstructured":"Gensluckner S, Wernly B, Datz C, Aigner E. Iron, oxidative stress, and metabolic dysfunction-associated steatotic liver disease. Antioxidants. 2024;13(2):208. https:\/\/doi.org\/10.3390\/antiox13020208.","journal-title":"Antioxidants"},{"key":"1356_CR33","doi-asserted-by":"publisher","first-page":"102164","DOI":"10.1016\/j.redox.2021.102164","volume":"47","author":"AD Read","year":"2021","unstructured":"Read AD, Bentley RE, Archer SL, Dunham-Snary KJ. Mitochondrial iron-sulfur clusters: structure, function, and an emerging role in vascular biology. Redox Biol. 2021;47:102164. https:\/\/doi.org\/10.1016\/j.redox.2021.102164.","journal-title":"Redox Biol"},{"key":"1356_CR34","doi-asserted-by":"publisher","unstructured":"Woodman AG, Mah R, Keddie D, Noble RMN, Panahi S, Gragasin FS, et al. Prenatal iron deficiency causes sex-dependent mitochondrial dysfunction and oxidative stress in fetal rat kidneys and liver. Faseb J. 2018;32(6):3254\u201363. https:\/\/doi.org\/10.1096\/fj.201701080R.","DOI":"10.1096\/fj.201701080R"},{"issue":"5","key":"1356_CR35","doi-asserted-by":"publisher","first-page":"319","DOI":"10.1002\/jcla.20335","volume":"23","author":"JH Yoo","year":"2009","unstructured":"Yoo JH, Maeng HY, Sun YK, Kim YA, Park DW, Park TS, et al. Oxidative status in iron-deficiency anemia. J Clin Lab Anal. 2009;23(5):319\u201323. https:\/\/doi.org\/10.1002\/jcla.20335.","journal-title":"J Clin Lab Anal"},{"issue":"3","key":"1356_CR36","doi-asserted-by":"publisher","first-page":"621","DOI":"10.1093\/jn\/130.3.621","volume":"130","author":"MD Knutson","year":"2000","unstructured":"Knutson MD, Walter PB, Ames BN, Viteri FE. Both iron deficiency and daily iron supplements increase lipid peroxidation in rats. J Nutr. 2000;130(3):621\u20138. https:\/\/doi.org\/10.1093\/jn\/130.3.621.","journal-title":"J Nutr"},{"issue":"23","key":"1356_CR37","doi-asserted-by":"publisher","first-page":"12948","DOI":"10.3390\/ijms222312948","volume":"22","author":"MJ Duryee","year":"2021","unstructured":"Duryee MJ, Clemens DL, Opperman PJ, Thiele GM, Duryee LM, Garvin RP, et al. Malondialdehyde-acetaldehyde modified (MAA) proteins differentially effect the inflammatory response in macrophage, endothelial cells and animal models of cardiovascular disease. Int J Mol Sci. 2021;22(23):12948. https:\/\/doi.org\/10.3390\/ijms222312948.","journal-title":"Int J Mol Sci"},{"issue":"17","key":"1356_CR38","doi-asserted-by":"publisher","first-page":"5718","DOI":"10.1093\/nar\/gkq212","volume":"38","author":"D Malhotra","year":"2010","unstructured":"Malhotra D, Portales-Casamar E, Singh A, Srivastava S, Arenillas D, Happel C, et al. Global mapping of binding sites for Nrf2 identifies novel targets in cell survival response through ChIP-seq profiling and network analysis. Nucleic Acids Res. 2010;38(17):5718\u201334. https:\/\/doi.org\/10.1093\/nar\/gkq212.","journal-title":"Nucleic Acids Res"},{"issue":"1","key":"1356_CR39","doi-asserted-by":"publisher","first-page":"76","DOI":"10.1101\/gad.13.1.76","volume":"13","author":"K Itoh","year":"1999","unstructured":"Itoh K, Wakabayashi N, Katoh Y, Ishii T, Igarashi K, Engel JD, et al. Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain. Genes Dev. 1999;13(1):76\u201386. https:\/\/doi.org\/10.1101\/gad.13.1.76.","journal-title":"Genes Dev"},{"issue":"3","key":"1356_CR40","doi-asserted-by":"publisher","first-page":"555","DOI":"10.3390\/antiox11030555","volume":"11","author":"SW Ryter","year":"2022","unstructured":"Ryter SW. Heme oxygenase-1: an anti-inflammatory effector in cardiovascular, lung, and related metabolic disorders. Antioxidants. 2022;11(3):555. https:\/\/doi.org\/10.3390\/antiox11030555.","journal-title":"Antioxidants"},{"issue":"10","key":"1356_CR41","doi-asserted-by":"publisher","first-page":"1011","DOI":"10.1056\/NEJMra041809","volume":"352","author":"G Weiss","year":"2005","unstructured":"Weiss G, Goodnough LT. Anemia of chronic disease. N Engl J Med. 2005;352(10):1011\u201323. https:\/\/doi.org\/10.1056\/NEJMra041809.","journal-title":"N Engl J Med"},{"issue":"40","key":"1356_CR42","doi-asserted-by":"publisher","first-page":"eabq5384","DOI":"10.1126\/sciadv.abq5384","volume":"8","author":"JN Frost","year":"2022","unstructured":"Frost JN, Wideman SK, Preston AE, Teh MR, Ai Z, Wang L, et al. Plasma iron controls neutrophil production and function. Sci Adv. 2022;8(40):eabq5384. https:\/\/doi.org\/10.1126\/sciadv.abq5384.","journal-title":"Sci Adv"},{"issue":"1","key":"1356_CR43","doi-asserted-by":"publisher","first-page":"66","DOI":"10.1139\/bcb-2020-0078","volume":"99","author":"Y Hao","year":"2021","unstructured":"Hao Y, Wang J, Teng D, Wang X, Mao R, Yang N, et al. A prospective on multiple biological activities of lactoferrin contributing to piglet welfare. Biochem Cell Biol. 2021;99(1):66\u201372. https:\/\/doi.org\/10.1139\/bcb-2020-0078.","journal-title":"Biochem Cell Biol"},{"issue":"3","key":"1356_CR44","doi-asserted-by":"publisher","first-page":"736","DOI":"10.1182\/blood-2011-02-337212","volume":"118","author":"A Pagani","year":"2011","unstructured":"Pagani A, Nai A, Corna G, Bosurgi L, Rovere-Querini P, Camaschella C, et al. Low hepcidin accounts for the proinflammatory status associated with iron deficiency. Blood. 2011;118(3):736\u201346. https:\/\/doi.org\/10.1182\/blood-2011-02-337212.","journal-title":"Blood"},{"key":"1356_CR45","doi-asserted-by":"publisher","first-page":"714613","DOI":"10.3389\/fimmu.2021.714613","volume":"12","author":"MR Teh","year":"2021","unstructured":"Teh MR, Frost JN, Armitage AE, Drakesmith H. Analysis of iron and iron-interacting protein dynamics during T-cell activation. Front Immunol. 2021;12:714613. https:\/\/doi.org\/10.3389\/fimmu.2021.714613.","journal-title":"Front Immunol"},{"key":"1356_CR46","doi-asserted-by":"publisher","first-page":"380","DOI":"10.1016\/j.aninu.2024.04.004","volume":"18","author":"G Liu","year":"2024","unstructured":"Liu G, Li L, Liu S, Dong Z, Zhou J, Gong C, et al. Characterization of serum proteomic and inflammatory profiling at early stage of iron deficiency in weaned piglets. Anim Nutr. 2024;18:380\u20139. https:\/\/doi.org\/10.1016\/j.aninu.2024.04.004.","journal-title":"Anim Nutr"},{"issue":"7","key":"1356_CR47","doi-asserted-by":"publisher","first-page":"1923","DOI":"10.1002\/eji.200738056","volume":"38","author":"M Nairz","year":"2008","unstructured":"Nairz M, Fritsche G, Brunner P, Talasz H, Hantke K, Weiss G. Interferon-gamma limits the availability of iron for intramacrophage Salmonella typhimurium. Eur J Immunol. 2008;38(7):1923\u201336. https:\/\/doi.org\/10.1002\/eji.200738056.","journal-title":"Eur J Immunol"},{"issue":"3","key":"1356_CR48","doi-asserted-by":"publisher","first-page":"969","DOI":"10.1084\/jem.180.3.969","volume":"180","author":"G Weiss","year":"1994","unstructured":"Weiss G, Werner-Felmayer G, Werner ER, Gr\u00fcnewald K, Wachter H, Hentze MW. Iron regulates nitric oxide synthase activity by controlling nuclear transcription. J Exp Med. 1994;180(3):969\u201376. https:\/\/doi.org\/10.1084\/jem.180.3.969.","journal-title":"J Exp Med"},{"key":"1356_CR49","doi-asserted-by":"publisher","first-page":"637809","DOI":"10.3389\/fimmu.2021.637809","volume":"12","author":"C Pfeifhofer-Obermair","year":"2021","unstructured":"Pfeifhofer-Obermair C, Tymoszuk P, Nairz M, Schroll A, Klais G, Demetz E, et al. Regulation of Th1 T cell differentiation by iron via upregulation of T cell immunoglobulin and mucin containing protein-3 (TIM-3). Front Immunol. 2021;12:637809. https:\/\/doi.org\/10.3389\/fimmu.2021.637809.","journal-title":"Front Immunol"},{"issue":"1","key":"1356_CR50","doi-asserted-by":"publisher","first-page":"273","DOI":"10.1002\/hep.24359","volume":"54","author":"E Corradini","year":"2011","unstructured":"Corradini E, Meynard D, Wu Q, Chen S, Ventura P, Pietrangelo A, et al. Serum and liver iron differently regulate the bone morphogenetic protein 6 (BMP6)-SMAD signaling pathway in mice. Hepatology. 2011;54(1):273\u201384. https:\/\/doi.org\/10.1002\/hep.24359.","journal-title":"Hepatology"},{"issue":"10","key":"1356_CR51","doi-asserted-by":"publisher","first-page":"2171","DOI":"10.1038\/s12276-024-01314-y","volume":"56","author":"D Davaanyam","year":"2024","unstructured":"Davaanyam D, Seol SI, Oh SA, Lee H, Lee JK. Hepatocyte activation and liver injury following cerebral ischemia promote HMGB1-mediated hepcidin upregulation in hepatocytes and regulation of systemic iron levels. Exp Mol Med. 2024;56(10):2171\u201383. https:\/\/doi.org\/10.1038\/s12276-024-01314-y.","journal-title":"Exp Mol Med"},{"key":"1356_CR52","doi-asserted-by":"publisher","unstructured":"Poltorak A, He X, Smirnova I, Liu MY, Van Huffel C, Du X, et al. Defective LPS signaling in C3H\/HeJ and C57BL\/10ScCr mice: mutations in Tlr4 gene. Science. 1998;282(5396):2085\u20138. https:\/\/doi.org\/10.1126\/science.282.5396.2085.","DOI":"10.1126\/science.282.5396.2085"},{"issue":"6","key":"1356_CR53","doi-asserted-by":"publisher","first-page":"837","DOI":"10.1016\/s1074-7613(00)80402-1","volume":"7","author":"H Wesche","year":"1997","unstructured":"Wesche H, Henzel WJ, Shillinglaw W, Li S, Cao Z. MyD88: an adapter that recruits IRAK to the IL-1 receptor complex. Immunity. 1997;7(6):837\u201347. https:\/\/doi.org\/10.1016\/s1074-7613(00)80402-1.","journal-title":"Immunity"},{"issue":"3","key":"1356_CR54","doi-asserted-by":"publisher","first-page":"227","DOI":"10.1002\/wsbm.1331","volume":"8","author":"S Mitchell","year":"2016","unstructured":"Mitchell S, Vargas J, Hoffmann A. Signaling via the NF\u03baB system. Wiley Interdiscip Rev Syst Biol Med. 2016;8(3):227\u201341. https:\/\/doi.org\/10.1002\/wsbm.1331.","journal-title":"Wiley Interdiscip Rev Syst Biol Med"},{"key":"1356_CR55","doi-asserted-by":"publisher","first-page":"3235","DOI":"10.2147\/jir.S343236","volume":"15","author":"M Saha","year":"2022","unstructured":"Saha M, Manna K, Das SK. Melatonin suppresses NLRP3 inflammasome activation via TLR4\/NF-\u03baB and P2X7R signaling in high-fat diet-induced murine NASH model. J Inflamm Res. 2022;15:3235\u201358. https:\/\/doi.org\/10.2147\/jir.S343236.","journal-title":"J Inflamm Res"},{"issue":"8","key":"1356_CR56","doi-asserted-by":"publisher","first-page":"1793","DOI":"10.1111\/j.1600-6143.2005.00932.x","volume":"5","author":"XD Shen","year":"2005","unstructured":"Shen XD, Ke B, Zhai Y, Gao F, Busuttil RW, Cheng G, et al. Toll-like receptor and heme oxygenase-1 signaling in hepatic ischemia\/reperfusion injury. Am J Transplant. 2005;5(8):1793\u2013800. https:\/\/doi.org\/10.1111\/j.1600-6143.2005.00932.x.","journal-title":"Am J Transplant"},{"issue":"3","key":"1356_CR57","doi-asserted-by":"publisher","first-page":"G433","DOI":"10.1152\/ajpgi.00163.2009","volume":"300","author":"T Csak","year":"2011","unstructured":"Csak T, Velayudham A, Hritz I, Petrasek J, Levin I, Lippai D, et al. Deficiency in myeloid differentiation factor-2 and toll-like receptor 4 expression attenuates nonalcoholic steatohepatitis and fibrosis in mice. Am J Physiol Gastrointest Liver Physiol. 2011;300(3):G433\u201341. https:\/\/doi.org\/10.1152\/ajpgi.00163.2009.","journal-title":"Am J Physiol Gastrointest Liver Physiol"},{"issue":"5","key":"1356_CR58","doi-asserted-by":"publisher","first-page":"e201900563","DOI":"10.26508\/lsa.201900563","volume":"2","author":"V Granatiero","year":"2019","unstructured":"Granatiero V, Konrad C, Bredvik K, Manfredi G, Kawamata H. Nrf2 signaling links ER oxidative protein folding and calcium homeostasis in health and disease. Life Sci Alliance. 2019;2(5):e201900563. https:\/\/doi.org\/10.26508\/lsa.201900563.","journal-title":"Life Sci Alliance"},{"issue":"4","key":"1356_CR59","doi-asserted-by":"publisher","first-page":"1025","DOI":"10.1007\/s00204-024-03681-x","volume":"98","author":"H Tang","year":"2024","unstructured":"Tang H, Kang R, Liu J, Tang D. ATF4 in cellular stress, ferroptosis, and cancer. Arch Toxicol. 2024;98(4):1025\u201341. https:\/\/doi.org\/10.1007\/s00204-024-03681-x.","journal-title":"Arch Toxicol"},{"key":"1356_CR60","doi-asserted-by":"publisher","unstructured":"Pei M, Deng K, Chen Y. Role and mechanism of endoplasmic reticulum stress and NLRP3 inflammasome in acute kidney injury.\u00a0J Cent South Univ (Med Sci). 2024;49(3):367\u2013376. https:\/\/doi.org\/10.11817\/j.issn.1672-7347.2024.230301.","DOI":"10.11817\/j.issn.1672-7347.2024.230301"},{"issue":"1","key":"1356_CR61","doi-asserted-by":"publisher","first-page":"346","DOI":"10.1186\/s12967-024-05156-0","volume":"22","author":"K Yang","year":"2024","unstructured":"Yang K, Xie R, Xiao G, Zhao Z, Ding M, Lin T, et al. The integration of single-cell and bulk RNA-seq atlas reveals ERS-mediated acinar cell damage in acute pancreatitis. J Transl Med. 2024;22(1):346. https:\/\/doi.org\/10.1186\/s12967-024-05156-0.","journal-title":"J Transl Med"},{"key":"1356_CR62","doi-asserted-by":"publisher","first-page":"739","DOI":"10.1146\/annurev.biochem.73.011303.074134","volume":"74","author":"M Schr\u00f6der","year":"2005","unstructured":"Schr\u00f6der M, Kaufman RJ. The mammalian unfolded protein response. Annu Rev Biochem. 2005;74:739\u201389. https:\/\/doi.org\/10.1146\/annurev.biochem.73.011303.074134.","journal-title":"Annu Rev Biochem"},{"issue":"7","key":"1356_CR63","doi-asserted-by":"publisher","first-page":"519","DOI":"10.1038\/nrm2199","volume":"8","author":"D Ron","year":"2007","unstructured":"Ron D, Walter P. Signal integration in the endoplasmic reticulum unfolded protein response. Nat Rev Mol Cell Biol. 2007;8(7):519\u201329. https:\/\/doi.org\/10.1038\/nrm2199.","journal-title":"Nat Rev Mol Cell Biol"},{"issue":"2","key":"1356_CR64","doi-asserted-by":"publisher","first-page":"58","DOI":"10.3390\/biomedicines6020058","volume":"6","author":"ML Schmitz","year":"2018","unstructured":"Schmitz ML, Shaban MS, Albert BV, G\u00f6k\u00e7en A, Kracht M. The crosstalk of endoplasmic reticulum (ER) stress pathways with NF-\u03baB: complex mechanisms relevant for cancer, inflammation and infection. Biomedicines. 2018;6(2):58. https:\/\/doi.org\/10.3390\/biomedicines6020058.","journal-title":"Biomedicines"},{"issue":"10","key":"1356_CR65","doi-asserted-by":"publisher","first-page":"e45078","DOI":"10.1371\/journal.pone.0045078","volume":"7","author":"AB Tam","year":"2012","unstructured":"Tam AB, Mercado EL, Hoffmann A, Niwa M. ER stress activates NF-\u03baB by integrating functions of basal IKK activity, IRE1 and PERK. PLoS ONE. 2012;7(10):e45078. https:\/\/doi.org\/10.1371\/journal.pone.0045078.","journal-title":"PLoS ONE"},{"issue":"6","key":"1356_CR66","doi-asserted-by":"publisher","first-page":"533","DOI":"10.2174\/1566524016666160523143937","volume":"16","author":"W Rozpedek","year":"2016","unstructured":"Rozpedek W, Pytel D, Mucha B, Leszczynska H, Diehl JA, Majsterek I. The role of the PERK\/eIF2\u03b1\/ATF4\/CHOP signaling pathway in tumor progression during endoplasmic reticulum stress. Curr Mol Med. 2016;16(6):533\u201344. https:\/\/doi.org\/10.2174\/1566524016666160523143937.","journal-title":"Curr Mol Med"},{"key":"1356_CR67","doi-asserted-by":"publisher","unstructured":"Chaudhari N, Talwar P, Parimisetty A, Lefebvre d\u2019Hellencourt CL, Ravanan P. A molecular web: endoplasmic reticulum stress, inflammation, and oxidative stress. Front Cell Neurosci. 2014;8:213. https:\/\/doi.org\/10.3389\/fncel.2014.00213.","DOI":"10.3389\/fncel.2014.00213"},{"key":"1356_CR68","doi-asserted-by":"publisher","unstructured":"Yamazaki H, Hiramatsu N, Hayakawa K, Tagawa Y, Okamura M, Ogata R, et al. Activation of the\u00a0Akt-NF-\u03baB\u00a0pathway by subtilase cytotoxin through the ATF6 branch of the unfolded protein response. J Immunol. 2009;183(2):1480\u20137. https:\/\/doi.org\/10.4049\/jimmunol.0900017.","DOI":"10.4049\/jimmunol.0900017"},{"issue":"7","key":"1356_CR69","doi-asserted-by":"publisher","first-page":"881","DOI":"10.1016\/s0092-8674(01)00611-0","volume":"107","author":"H Yoshida","year":"2001","unstructured":"Yoshida H, Matsui T, Yamamoto A, Okada T, Mori K. XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor. Cell. 2001;107(7):881\u201391. https:\/\/doi.org\/10.1016\/s0092-8674(01)00611-0.","journal-title":"Cell"},{"key":"1356_CR70","doi-asserted-by":"publisher","unstructured":"Baeuerle PA, Henkel T. Function and activation of\u00a0NF-\u03baB\u00a0in the immune system. Annu Rev Immunol. 1994;12:141\u201379. https:\/\/doi.org\/10.1146\/annurev.iy.12.040194.001041.","DOI":"10.1146\/annurev.iy.12.040194.001041"},{"key":"1356_CR71","doi-asserted-by":"publisher","first-page":"7295224","DOI":"10.1155\/2022\/7295224","volume":"2022","author":"Y Zhang","year":"2022","unstructured":"Zhang Y, Yang G, Huang S, Yang X, Yuan F, Song Y, et al. Regulation of Cr(VI)-induced premature senescence in L02 hepatocytes by ROS-Ca(2+)-NF-\u03baB signaling. Oxid Med Cell Longev. 2022;2022:7295224. https:\/\/doi.org\/10.1155\/2022\/7295224.","journal-title":"Oxid Med Cell Longev"},{"issue":"3","key":"1356_CR72","doi-asserted-by":"publisher","first-page":"L483","DOI":"10.1152\/ajplung.00212.2019","volume":"318","author":"J Yap","year":"2020","unstructured":"Yap J, Chen X, Delmotte P, Sieck GC. Tnf\u03b1 selectively activates the IRE1\u03b1\/XBP1 endoplasmic reticulum stress pathway in human airway smooth muscle cells. Am J Physiol Lung Cell Mol Physiol. 2020;318(3):L483-l493. https:\/\/doi.org\/10.1152\/ajplung.00212.2019.","journal-title":"Am J Physiol Lung Cell Mol Physiol"},{"issue":"40","key":"1356_CR73","doi-asserted-by":"publisher","first-page":"33917","DOI":"10.1074\/jbc.M505818200","volume":"280","author":"X Xue","year":"2005","unstructured":"Xue X, Piao J-H, Nakajima A, Sakon-Komazawa S, Kojima Y, Mori K, et al. Tumor necrosis factor \u03b1 (TNF\u03b1) induces the unfolded protein response (UPR) in a reactive oxygen species (ROS)-dependent fashion, and the UPR counteracts ROS accumulation by TNF\u03b1. J Biol Chem. 2005;280(40):33917\u201325. https:\/\/doi.org\/10.1074\/jbc.M505818200.","journal-title":"J Biol Chem"},{"issue":"3","key":"1356_CR74","doi-asserted-by":"publisher","first-page":"587","DOI":"10.1016\/j.cell.2005.11.040","volume":"124","author":"K Zhang","year":"2006","unstructured":"Zhang K, Shen X, Wu J, Sakaki K, Saunders T, Rutkowski DT, et al. Endoplasmic reticulum stress activates cleavage of CREBH to induce a systemic inflammatory response. Cell. 2006;124(3):587\u201399. https:\/\/doi.org\/10.1016\/j.cell.2005.11.040.","journal-title":"Cell"},{"issue":"5","key":"1356_CR75","doi-asserted-by":"publisher","first-page":"e36408","DOI":"10.1371\/journal.pone.0036408","volume":"7","author":"Y Lin","year":"2012","unstructured":"Lin Y, Jamison S, Lin W. Interferon-\u03b3 activates nuclear factor-\u03ba B in oligodendrocytes through a process mediated by the unfolded protein response. PLoS ONE. 2012;7(5):e36408. https:\/\/doi.org\/10.1371\/journal.pone.0036408.","journal-title":"PLoS ONE"}],"container-title":["Journal of Animal Science and Biotechnology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s40104-026-01356-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s40104-026-01356-4","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s40104-026-01356-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,13]],"date-time":"2026-02-13T00:03:40Z","timestamp":1770941020000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1186\/s40104-026-01356-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,13]]},"references-count":75,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["1356"],"URL":"https:\/\/doi.org\/10.1186\/s40104-026-01356-4","relation":{"has-preprint":[{"id-type":"doi","id":"10.21203\/rs.3.rs-7787366\/v1","asserted-by":"object"}]},"ISSN":["2049-1891"],"issn-type":[{"value":"2049-1891","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,13]]},"assertion":[{"value":"6 October 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"9 January 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"13 February 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The animal study protocol was conducted following guidelines authorized by the Animal Ethics Committee of Nanjing Agricultural University (Permit number SYXK-2017-0027).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"All authors read and agree to the content of this paper and its publication.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"30"}}