{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T04:41:42Z","timestamp":1790311302574,"version":"4.1.0"},"reference-count":45,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2024,8,31]],"date-time":"2024-08-31T00:00:00Z","timestamp":1725062400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"Natural Science Foundation of Hubei Province","doi-asserted-by":"publisher","award":["2019CFB500"],"award-info":[{"award-number":["2019CFB500"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Toxics"],"abstract":"<jats:p>Prolonged exposure to hydroquinone (HQ), a metabolite of benzene, can cause severe haematologic disorders in humans. However, the mechanism is still unclear. In the present study, we investigated whether HQ can induce haematological diseases through ferroptosis, which is another form of cell death apart from apoptosis. The results showed that HQ inhibited the viability of Jurkat cells in a dose-dependent and time-dependent manner. The half inhibitory concentrations (IC50s) of HQ-treated Jurkat cells for 12 h, 24 h and 48 h were 107.16 \u03bcmol\/L, 33.29 \u03bcmol\/L, and 14.78 \u03bcmol\/L. The exposure of Jurkat cells to HQ increased intracellular Fe2+, malondialdehyde (MDA) and lipid reactive oxygen species (ROS) levels and down-regulated glutathione (GSH) levels. We used erastin-treated cells as a positive control and cells treated with HQ combined with deferoxamine mesylate (DFO) and ferrostain-1 (Fer-1)-treated cells as the negative controls. DFO and Fer-1 partially restored the degradation of cell viability and GSH content and the accumulation of Fe2+, MDA and lipid ROS caused by HQ. In addition, we found that cellular mitochondria in the HQ-treated group showed a decrease in volume, an increase in the density of the bilayer membrane and a decrease or disappearance of mitochondrial cristae. Changes in the erastin-treated group were similar to those in the HQ-treated group. We inferred that HQ induces ferroptosis in Jurkat cells. Subsequently, we found that HQ up-regulated the levels of transferrin receptor 1 (TFRC) mRNA and protein expression and down-regulated FTH1, SLC7A11 and synthetic substrate of antioxidant enzyme 4 (GPX4) mRNA levels and protein expression levels. However, the exposure of Jurkat cells to HQ with DFO and Fer-1 alleviated these changes. Notably, the activation of TFRC and the inhibition of FTH1 and System Xc\u2212 (cystine\u2013glutamate reverse transporter protein) \/GPX4 were associated with HQ-induced ferroptosis. These results provide novel insights into how HQ exacerbates haematopoietic cytotoxicity and provide potential targets for the prevention of HQ-induced diseases.<\/jats:p>","DOI":"10.3390\/toxics12090644","type":"journal-article","created":{"date-parts":[[2024,9,2]],"date-time":"2024-09-02T12:54:42Z","timestamp":1725281682000},"page":"644","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Effects on Iron Metabolism and System Xc\u2212 \/GPX4 Pathway from Hydroquinone Suggest Ferroptosis of Jurkat Cells"],"prefix":"10.3390","volume":"12","author":[{"given":"Nana","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Occupational and Environmental Health, School of Public Health, Wuhan University, Wuhan 430071, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ge","family":"Liu","sequence":"additional","affiliation":[{"name":"Wuhan Center for Disease Control & Prevention, Wuhan 430000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiang","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Occupational and Environmental Health, School of Public Health, Wuhan University, Wuhan 430071, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yipeng","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Occupational and Environmental Health, School of Public Health, Wuhan University, Wuhan 430071, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7540-5254","authenticated-orcid":false,"given":"Hong","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Occupational and Environmental Health, School of Public Health, Wuhan University, Wuhan 430071, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,8,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"837","DOI":"10.1182\/blood.V44.6.837.837","article-title":"Leukemia in shoe-workers exposed chronically to benzene","volume":"44","author":"Aksoy","year":"1974","journal-title":"Blood"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1186\/1476-069X-9-31","article-title":"Exposure to benzene at work and the risk of leukemia: A systematic review and meta-analysis","volume":"9","author":"Khalade","year":"2010","journal-title":"Environ. Health"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"9626","DOI":"10.1007\/s11356-021-17432-3","article-title":"Research development and trends of benzene-induced leukemia from 1990 to 2019-A bibliometric analysis","volume":"29","author":"Sun","year":"2022","journal-title":"Environ. Sci. Pollut. Res. Int."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1182\/blood.V79.3.627.627","article-title":"Induced differentiation of HL-60 promyelocytic leukemia cells to monocyte\/macrophages is inhibited by hydroquinone, a hematotoxic metabolite of benzene","volume":"79","author":"Oliveira","year":"1992","journal-title":"Blood"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1022","DOI":"10.1111\/jcmm.14003","article-title":"Benzene induces haematotoxicity by promoting deacetylation and autophagy","volume":"23","author":"Qian","year":"2019","journal-title":"J. Cell Mol. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"114147","DOI":"10.1016\/j.envpol.2020.114147","article-title":"Regulatory loop between lncRNA FAS-AS1 and DNMT3b controls FAS expression in hydroquinone-treated TK6 cells and benzene-exposed workers","volume":"261","author":"Yuan","year":"2020","journal-title":"Environ. Pollut."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1060","DOI":"10.1016\/j.cell.2012.03.042","article-title":"Ferroptosis: An iron-dependent form of nonapoptotic cell death","volume":"149","author":"Dixon","year":"2012","journal-title":"Cell"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1038\/s41580-020-00324-8","article-title":"Ferroptosis: Mechanisms, biology and role in disease","volume":"22","author":"Jiang","year":"2021","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_9","first-page":"382","article-title":"Nrf2 sensitizes ferroptosis through l-2-hydroxyglutarate-mediated chromatin modifications in sickle cell disease","volume":"142","author":"Xi","year":"2023","journal-title":"Blood"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"165678","DOI":"10.1016\/j.scitotenv.2023.165678","article-title":"Probiotics ameliorate benzene-induced systemic inflammation and hematopoietic toxicity by inhibiting Bacteroidaceae-mediated ferroptosis","volume":"899","author":"Zhang","year":"2023","journal-title":"Sci. Total Environ."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"418","DOI":"10.1038\/nature25022","article-title":"From haematopoietic stem cells to complex differentiation landscapes","volume":"553","author":"Laurenti","year":"2018","journal-title":"Nature"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1384","DOI":"10.1016\/j.cell.2020.08.030","article-title":"Unraveling Hematopoiesis through the Lens of Genomics","volume":"182","author":"Liggett","year":"2020","journal-title":"Cell"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"732","DOI":"10.1016\/j.cell.2023.01.020","article-title":"Human hematopoietic stem cell vulnerability to ferroptosis","volume":"186","author":"Zhao","year":"2023","journal-title":"Cell"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Bhattarai, N., Korhonen, E., Mysore, Y., Kaarniranta, K., and Kauppinen, A. (2021). Hydroquinone induces NLRP3-independent IL-18 release from ARPE-19 cells. Cells, 10.","DOI":"10.3390\/cells10061405"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Bhattarai, N., Korhonen, E., Toppila, M., Koskela, A., Kaarniranta, K., Mysore, Y., and Kauppinen, A. (2020). Resvega alleviates hydroquinone-induced oxidative stress in ARPE-19 cells. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21062066"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Hayashi, S., Nakamura, T., Motooka, Y., Ito, F., Jiang, L., Akatsuka, S., Iwase, A., Kajiyama, H., Kikkawa, F., and Toyokuni, S. (2020). Novel ovarian endometriosis model causes infertility via iron-mediated oxidative stress in mice. Redox Biol., 37.","DOI":"10.1016\/j.redox.2020.101726"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1016\/j.freeradbiomed.2022.08.018","article-title":"Iron overload promotes intervertebral disc degeneration via inducing oxidative stress and ferroptosis in endplate chondrocytes","volume":"190","author":"Wang","year":"2022","journal-title":"Free Radic. Biol. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/j.canlet.2011.07.024","article-title":"Disruption of xCT inhibits cell growth via the ROS\/autophagy pathway in hepatocellular carcinoma","volume":"312","author":"Guo","year":"2011","journal-title":"Cancer Lett."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1589","DOI":"10.1038\/s41467-021-21841-w","article-title":"mTORC1 couples cyst(e)ine availability with GPX4 protein synthesis and ferroptosis regulation","volume":"12","author":"Zhang","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1038\/nature24297","article-title":"Drug-tolerant persister cancer cells are vulnerable to GPX4 inhibition","volume":"551","author":"Hangauer","year":"2017","journal-title":"Nature"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1038\/s41422-020-00441-1","article-title":"Ferroptosis: Molecular mechanisms and health implications","volume":"31","author":"Tang","year":"2021","journal-title":"Cell Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1016\/j.cell.2013.12.010","article-title":"Regulation of ferroptotic cancer cell death by GPX4","volume":"156","author":"Yang","year":"2014","journal-title":"Cell"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1038\/s41467-020-14324-x","article-title":"Nedd4 ubiquitylates VDAC2\/3 to suppress erastin-induced ferroptosis in melanoma","volume":"11","author":"Yang","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"5617","DOI":"10.1038\/onc.2015.32","article-title":"HSPB1 as a novel regulator of ferroptotic cancer cell death","volume":"34","author":"Sun","year":"2015","journal-title":"Oncogene"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1016\/j.canlet.2020.02.015","article-title":"Ferroptosis, a novel pharmacological mechanism of anti-cancer drugs","volume":"483","author":"Su","year":"2020","journal-title":"Cancer Lett."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Pei, Z., Qin, Y., Fu, X., Yang, F., Huo, F., Liang, X., Wang, S., Cui, H., Lin, P., and Zhou, G. (2022). Inhibition of ferroptosis and iron accumulation alleviates pulmonary fibrosis in a bleomycin model. Redox Biol., 57.","DOI":"10.1016\/j.redox.2022.102509"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"4045","DOI":"10.1016\/j.apsb.2021.03.036","article-title":"Baicalin induces ferroptosis in bladder cancer cells by downregulating FTH1","volume":"11","author":"Kong","year":"2021","journal-title":"Acta Pharm. Sin. B"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1007\/s10565-013-9247-0","article-title":"Genotoxicity of hydroquinone in A549 cells","volume":"29","author":"Peng","year":"2013","journal-title":"Cell Biol. Toxicol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"818","DOI":"10.1093\/carcin\/bgs409","article-title":"p38 MAPK\/PP2Acalpha\/TTP pathway on the connection of TNF-alpha and caspases activation on hydroquinone-induced apoptosis","volume":"34","author":"Liu","year":"2013","journal-title":"Carcinogenesis"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"114389","DOI":"10.1016\/j.ecoenv.2022.114389","article-title":"Nrf2 affects hydroquinone-induces cell cycle arrest through the p16\/pRb signaling pathway and antioxidant enzymes","volume":"249","author":"Chen","year":"2023","journal-title":"Ecotoxicol. Environ. Saf."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1006\/taap.2001.9221","article-title":"Differential involvement of caspases in hydroquinone-induced apoptosis in human leukemic hl-60 and jurkat cells","volume":"175","author":"Winski","year":"2001","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2207","DOI":"10.1007\/s10565-022-09705-5","article-title":"Effects of SIDT2 on the miR-25\/NOX4\/HuR axis and SIRT3 mRNA stability lead to ROS-mediated TNF-alpha expression in hydroquinone-treated leukemia cells","volume":"39","author":"Wang","year":"2023","journal-title":"Cell Biol. Toxicol."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Yu, C.H., Yang, S.Q., Li, L., Xin, Y., Zhang, F., Liu, X.F., and Yi, Z.C. (2022). Identification of potential pathways and microRNA-mRNA networks associated with benzene metabolite hydroquinone-induced hematotoxicity in human leukemia K562 cells. BMC Pharmacol. Toxicol., 23.","DOI":"10.1186\/s40360-022-00556-8"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"230182","DOI":"10.1155\/2015\/230182","article-title":"Iron-induced damage in cardiomyopathy: Oxidative-dependent and independent mechanisms","volume":"2015","author":"Gammella","year":"2015","journal-title":"Oxid. Med. Cell Longev."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"63779","DOI":"10.18632\/oncotarget.11687","article-title":"RSL3 and Erastin differentially regulate redox signaling to promote Smac mimetic-induced cell death","volume":"7","author":"Dachert","year":"2016","journal-title":"Oncotarget"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"4551","DOI":"10.1021\/ja411006a","article-title":"Ferrostatins inhibit oxidative lipid damage and cell death in diverse disease models","volume":"136","author":"Skouta","year":"2014","journal-title":"J. Am. Chem. Soc."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"951","DOI":"10.1093\/humrep\/deaa363","article-title":"Erastin induces ferroptosis via ferroportin-mediated iron accumulation in endometriosis","volume":"36","author":"Li","year":"2021","journal-title":"Hum. Reprod."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1016\/j.canlet.2017.12.025","article-title":"Heme oxygenase-1 mediates BAY 11-7085 induced ferroptosis","volume":"416","author":"Chang","year":"2018","journal-title":"Cancer Lett."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1016\/j.molcel.2015.06.011","article-title":"Glutaminolysis and Transferrin Regulate Ferroptosis","volume":"59","author":"Gao","year":"2015","journal-title":"Mol. Cell"},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Wang, Y.Q., Chang, S.Y., Wu, Q., Gou, Y.J., Jia, L., Cui, Y.M., Yu, P., Shi, Z.H., Wu, W.S., and Gao, G. (2016). The Protective Role of Mitochondrial Ferritin on Erastin-Induced Ferroptosis. Front. Aging Neurosci., 8.","DOI":"10.3389\/fnagi.2016.00308"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1038\/s41580-023-00648-1","article-title":"Mechanisms controlling cellular and systemic iron homeostasis","volume":"25","author":"Galy","year":"2024","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1016\/S1097-2765(00)80282-8","article-title":"IRP-1 binding to ferritin mRNA prevents the recruitment of the small ribosomal subunit by the cap-binding complex eIF4F","volume":"2","author":"Muckenthaler","year":"1998","journal-title":"Mol. Cell"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1614","DOI":"10.1016\/j.celrep.2017.05.009","article-title":"Regnase-1 Maintains Iron Homeostasis via the Degradation of Transferrin Receptor 1 and Prolyl-Hydroxylase-Domain-Containing Protein 3 mRNAs","volume":"19","author":"Yoshinaga","year":"2017","journal-title":"Cell Rep."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"3015","DOI":"10.1007\/s10565-023-09815-8","article-title":"GPR116 promotes ferroptosis in sepsis-induced liver injury by suppressing system Xc\u2212\/GSH\/GPX4","volume":"39","author":"Wang","year":"2023","journal-title":"Cell Biol. Toxicol."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"He, Q., Yang, J., Pan, Z., Zhang, G., Chen, B., Li, S., Xiao, J., Tan, F., Wang, Z., and Chen, P. (2023). Biochanin A protects against iron overload associated knee osteoarthritis via regulating iron levels and NRF2\/System Xc\u2212\/GPX4 axis. Biomed. Pharmacother., 157.","DOI":"10.1016\/j.biopha.2022.113915"}],"container-title":["Toxics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2305-6304\/12\/9\/644\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T15:46:21Z","timestamp":1760111181000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2305-6304\/12\/9\/644"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,8,31]]},"references-count":45,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2024,9]]}},"alternative-id":["toxics12090644"],"URL":"https:\/\/doi.org\/10.3390\/toxics12090644","relation":{},"ISSN":["2305-6304"],"issn-type":[{"value":"2305-6304","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,8,31]]}}}