This study investigated how non-hepatic surgery and subsequent acute stress affect iron distribution, redox state, antioxidant defence, and inflammation-related gene expressions and iron metabolism in the liver of borderline hypertensive rats. We used air-jet stress as a model of acute psychological stress (3 sessions of 5 sec. air-jet) applied approximately 22 hours post-surgery (carotid artery and jugular vein cannulation). Both the surgery (Su) and post-surgical stress (Su+Str) increased corticosterone and reduced iron concentrations in plasma, while increasing remanent magnetisation (Mr) and coercivity (Hc) in whole blood. In the liver, Su and Su+Str reduced mRNA expressions of genes encoding NFR2 and GPX4 proteins (Nfe2l2 and Gpx4, respectively), and induced a significant increase in hepatic conjugated dienes, proinflammatory factors (Il1b) and iron-regulating genes mRNA (Hmox1, Fpn1, Fth1, Hamp, Tfr1), despite elevated Hmox1 and Sod1 mRNA expressions. In addition, hepatic Mr and Hc after Su and Su+Str were elevated, suggesting a qualitative change of iron-containing substances in circulation and liver tissue. In addition, in the Su+Str group, the elevated saturation magnetisation (Ms) is indicative of elevated total iron content. These findings suggest that a mild non-hepatic surgery may reduce hepatic mRNA expression of NRF2 and GPX4, which was associated with oxidative tissue damage accompanied by qualitative alterations in cellular iron, indicating a pro-ferroptotic state that, together with enhanced inflammation, may contribute to post-surgical liver injury. Additionally, the combination of surgery and acute post-surgical stress led to tissue iron accumulation, which may contribute to liver damage.

Centre of Experimental Medicine Slovak Academy of Sciences Institute of Normal and Pathological Physiology Bratislava Slovakia

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Ivascu R, Torsin LI, Hostiuc L, Nitipir C, Corneci D, Dutu M. The surgical stress response and anesthesia: a narrative review. J Clin Med. 2024;13:3017. doi: 10.3390/jcm13103017. PubMed DOI PMC

Wax DB, Porter SB, Lin HM, Hossain S, Reich DL. Association of preanesthesia hypertension with adverse outcomes. J Cardiothorac Vasc Anesth. 2010;24:927–930. doi: 10.1053/j.jvca.2010.06.022. PubMed DOI

Egan BM, Stevens-Fabry S. Prehypertension-prevalence, health risks, and management strategies. Nat Rev Cardiol. 2015;12:289–300. doi: 10.1038/nrcardio.2015.17. PubMed DOI

Kluknavsky M, Balis P, Skratek M, Manka J, Bernatova I. (−)-Epicatechin reduces the blood pressure of young borderline hypertensive rats during the post-treatment period. Antioxidants. 2020;9:96. doi: 10.3390/antiox9020096. PubMed DOI PMC

Šarenac O, Lozić M, Drakulić S, Bajić D, Paton JF, Murphy D, et al. Autonomic mechanisms underpinning the stress response in borderline hypertensive rats. Exp Physiol. 2011;96:574–589. doi: 10.1113/expphysiol.2010.055970. PubMed DOI PMC

Zhao M, Chen J, Wang W, Wang L, Ma L, Shen H, et al. Psychological stress induces hypoferremia through the IL-6-hepcidin axis in rats. Biochem Biophys Res Commun. 2008;373:90–93. doi: 10.1016/j.bbrc.2008.05.166. PubMed DOI

Li Y, Zheng Y, Qian J, Chen X, Shen Z, Tao L, et al. Preventive effects of zinc against psychological stress-induced iron dyshomeostasis, erythropoiesis inhibition, and oxidative stress status in rats. Biol Trace Elem Res. 2012;147:285–291. doi: 10.1007/s12011-011-9319-z. PubMed DOI

Kasahara E, Nakamura A, Morimoto K, Ito S, Hori M, Sekiyama A. Social defeat stress impairs systemic iron metabolism by activating the hepcidin-ferroportin axis. FASEB Bioadv. 2024;6:263–275. doi: 10.1096/fba.2024-00071. PubMed DOI PMC

Hortová-Kohoutková M, Skotáková M, Onyango IG, Slezáková M, Panovský R, Opatřil L, et al. Hepcidin and ferritin levels as markers of immune cell activation during septic shock, severe COVID-19 and sterile inflammation. Front Immunol. 2023;14:1110540. doi: 10.3389/fimmu.2023.1110540. PubMed DOI PMC

Piagnerelli M, Cotton F, Herpain A, Rapotec A, Chatti R, Gulbis B, et al. Time course of iron metabolism in critically ill patients. Acta Clin Belg. 2013;68:22–27. doi: 10.2143/ACB.68.1.2062715. PubMed DOI

Pagani A, Nai A, Silvestri L, Camaschella C. Hepcidin and anemia: a tight relationship. Front Physiol. 2019;10:1294. doi: 10.3389/fphys.2019.01294. PubMed DOI PMC

Gensluckner S, Wernly B, Datz C, Aigner E. Iron, oxidative stress, and metabolic dysfunction-associated steatotic liver disease. Antioxidants. 2024;13:208. doi: 10.3390/antiox13020208. PubMed DOI PMC

Vnukov V, Gutsenko O, Milyutina N, Kornienko I, Ananyan A, Plotnikov A, et al. SkQ1 regulates expression of Nrf2, ARE-controlled genes encoding antioxidant enzymes, and their activity in cerebral cortex under oxidative stress. Biochemistry (Mosc) 2017;82:942–952. doi: 10.1134/S0006297917080090. PubMed DOI

Tian X, Li Y, Lei L, Feng X, Xin H, Chen H, et al. The tf/Nrf2/GSTP1 pathway is involved in stress-induced hepatocellular injury through ferroptosis. J Cell Mol Med. 2024;28:e18494. doi: 10.1111/jcmm.18494. PubMed DOI PMC

Behuliak M, Pintérová M, Bencze M, Petrová M, Líšková S, Karen P, et al. Ca2+ sensitization and Ca2+ entry in the control of blood pressure and adrenergic vasoconstriction in conscious Wistar-Kyoto and spontaneously hypertensive rats. J Hypertens. 2013;31:2025–2035. doi: 10.1097/HJH.0b013e328362adb3. PubMed DOI

Líšková S, Bališ P, Mičurová A, Kluknavský M, Okuliarová M, Puzserová A, et al. Effect of iron oxide nanoparticles on vascular function and nitric oxide production in acute stress-exposed rats. Physiol Res. 2020;69:1067. doi: 10.33549/physiolres.934567. PubMed DOI PMC

Song H, Zhang S, Sun X, Liu J, Wu Y, Guo W, et al. Distinct iron deposition profiles of liver zones in various models with iron homeostasis disorders. Adv Sci. 2018;5:1800866. doi: 10.1002/advs.201800866. PubMed DOI PMC

Puzserova A, Slezak P, Balis P, Bernatova I. Long-term social stress induces nitric oxide-independent endothelial dysfunction in normotensive rats. Stress. 2013;16:331–339. doi: 10.3109/10253890.2012.725116. PubMed DOI

Škrátek M, Dvurečenskij A, Kluknavský M, Barta A, Bališ P, Mičurová A, et al. Sensitive SQUID bio-magnetometry for determination and differentiation of biogenic iron and iron oxide nanoparticles in biological samples. Nanomaterials. 2020;10:1993. doi: 10.3390/nano10101993. PubMed DOI PMC

Kluknavsky M, Micurova A, Cebova M, Şaman E, Cacanyiova S, Bernatova I. MLN-4760 induces oxidative stress without blood pressure and behavioural alterations in SHRs: roles of Nfe2l2 gene, nitric oxide and hydrogen sulfide. Antioxidants. 2022;11:2385. doi: 10.3390/antiox11122385. PubMed DOI PMC

Díaz-Muñoz M, Vázquez-Martínez O, Báez-Ruiz A, Martínez-Cabrera G, Soto-Abraham MV, Ávila-Casado MC, et al. Daytime food restriction alters liver glycogen, triacylglycerols, and cell size: a histochemical, morphometric, and ultrastructural study. Comp Hepatol. 2010;9:5. doi: 10.1186/1476-5926-9-5. PubMed DOI PMC

Larkin LM, Horwitz BA, McDonald RB. Effect of cold on serum substrate and glycogen concentration in young and old Fischer 344 rats. Exp Gerontol. 1992;27:179–190. doi: 10.1016/0531-5565(92)90042-X. PubMed DOI PMC

Boshuizen M, Binnekade JM, Nota B, van de Groep K, Cremer OL, Tuinman PR, et al. Iron metabolism in critically ill patients developing anemia of inflammation: a case control study. Ann Intensive Care. 2018;8:56. doi: 10.1186/s13613-018-0407-5. PubMed DOI PMC

Cherry-Bukowiec JR, Engoren M, Wiktor A, Raghavendran K, Napolitano LM. Hepcidin and anemia in surgical critical care: a prospective cohort study. Crit Care Med. 2018;46(6):e567–74. doi: 10.1097/CCM.0000000000003089. PubMed DOI

Stoffel NU, Lazrak M, Bellitir S, El Mir N, El Hamdouchi A, Barkat A, et al. The opposing effects of acute inflammation and iron deficiency anemia on serum hepcidin and iron absorption in young women. Haematologica. 2019;104:1143. doi: 10.3324/haematol.2018.208645. PubMed DOI PMC

Tandara L, Salamunić I. Iron metabolism: current facts and future directions. Biochem Med (Zagreb) 2012;22:311–28. doi: 10.11613/BM.2012.034. PubMed DOI PMC

Grassi-Schultheiss P, Heller F, Dobson J. Analysis of magnetic material in the human heart, spleen and liver. Biometals. 1997;10:351–355. doi: 10.1023/A:1018340920329. PubMed DOI

Everett J, Brooks J, Lermyte F, O’Connor PB, Sadler PJ, Dobson J, et al. Iron stored in ferritin is chemically reduced in the presence of aggregating Aβ(1–42) Sci Rep. 2020;10:10332. doi: 10.1038/s41598-020-67117-z. PubMed DOI PMC

Gong K, Liang K, Li H, Luo H, Chen Y, Yin K, et al. Oxidative ferritin destruction: a key mechanism of iron overload in acetaminophen-induced hepatocyte ferroptosis. Int J Mol Sci. 2025;26:7585. doi: 10.3390/ijms26157585. PubMed DOI PMC

Shivaswamy V, Ramakrishna Kurup C, Ramasarma T. Ferrous-iron induces lipid peroxidation with little damage to energy transduction in mitochondria. Mol Cell Biochem. 1993;120:141–149. doi: 10.1007/BF00926087. PubMed DOI

Liu Y, Li F, Zhang L, Wu J, Wang Y, Yu H. Taurine alleviates lipopolysaccharide-induced liver injury by anti-inflammation and antioxidants in rats. Mol Med Rep. 2017;16:6512–6517. doi: 10.3892/mmr.2017.7414. PubMed DOI PMC

Malik IA, Naz N, Sheikh N, Khan S, Moriconi F, Blaschke M, et al. Comparison of changes in gene expression of transferrin receptor-1 and other iron-regulatory proteins in rat liver and brain during acute-phase response. Cell Tissue Res. 2011;344:299–312. doi: 10.1007/s00441-011-1152-3. PubMed DOI PMC

Christiansen H, Sheikh N, Saile B, Reuter F, Rave-Frank M, Hermann RM, et al. X-irradiation in rat liver: consequent upregulation of hepcidin and downregulation of hemojuvelin and ferroportin-1 gene expression. Radiology. 2007;242:189–197. doi: 10.1148/radiol.2421060083. PubMed DOI

Naz N, Malik IA, Sheikh N, Ahmad S, Khan S, Blaschke M, et al. Ferroportin-1 is a ‘nuclear’-negative acute-phase protein in rat liver: a comparison with other iron-transport proteins. Lab Invest. 2012;92:842–856. doi: 10.1038/labinvest.2012.52. PubMed DOI

Stockwell BR, Angeli JPF, Bayir H, Bush AI, Conrad M, Dixon SJ, et al. Ferroptosis: a regulated cell death nexus linking metabolism, redox biology, and disease. Cell. 2017;171:273–285. doi: 10.1016/j.cell.2017.09.021. PubMed DOI PMC

Chen HJC, Yip T, Lee JK, Juliani J, Sernia C, Hill AF, et al. Restraint stress alters expression of glucocorticoid bioavailability mediators, suppresses Nrf2, and promotes oxidative stress in liver tissue. Antioxidants. 2020;9:853. doi: 10.3390/antiox9090853. PubMed DOI PMC

Ge M, Yao W, Wang Y, Yuan D, Chi X, Luo G, et al. Propofol alleviates liver oxidative stress via activating Nrf2 pathway. J Surg Res. 2015;196:373–381. doi: 10.1016/j.jss.2015.03.016. PubMed DOI

Kwak MK, Itoh K, Yamamoto M, Kensler TW. Enhanced expression of the transcription factor Nrf2 by cancer chemopreventive agents: role of antioxidant response element-like sequences in the Nrf2 promoter. Mol Cell Biol. 2002;22:2883–2892. doi: 10.1128/MCB.22.9.2883-2892.2002. PubMed DOI PMC

Chang CK, Llanes S, Schumer W. Effect of dexamethasone on NF-κB activation, tumor necrosis factor formation, and glucose dyshomeostasis in septic rats. J Surg Res. 1997;72:141–145. doi: 10.1006/jsre.1997.5173. PubMed DOI

González MV, Jiménez B, Berciano MT, González-Sancho JM, Caelles C, Lafarga M, et al. Glucocorticoids antagonize AP-1 by inhibiting the activation/phosphorylation of JNK without affecting its subcellular distribution. J Cell Biol. 2000;150:1199–1208. doi: 10.1083/jcb.150.5.1199. PubMed DOI PMC

Sheikh N, Batusic DS, Dudas J, Tron K, Neubauer K, Saile B, et al. Hepcidin and hemojuvelin gene expression in rat liver damage: in vivo and in vitro studies. Am J Physiol Gastrointest Liver Physiol. 2006;291:G482–G490. doi: 10.1152/ajpgi.00586.2005. PubMed DOI

Spiers JG, Steiger N, Khadka A, Juliani J, Hill AF, Lavidis NA, et al. Repeated acute stress modulates hepatic inflammation and markers of macrophage polarisation in the rat. Biochimie. 2021;180:30–42. doi: 10.1016/j.biochi.2020.10.014. PubMed DOI

Gong P, Cederbaum AI. Nrf2 is increased by CYP2E1 in rodent liver and HepG2 cells and protects against oxidative stress caused by CYP2E1. Hepatology. 2006;43:144–153. doi: 10.1002/hep.21004. PubMed DOI