Erastin‑induced ferroptosis causes physiological and pathological changes in healthy tissues of mice

Zhao,Jing; Xu,Ben; Xiong,Qingqing; Feng,Yunfei; Du,Huahua

doi:10.3892/mmr.2021.12352

Erastin‑induced ferroptosis causes physiological and pathological changes in healthy tissues of mice

Authors:
- Jing Zhao
- Ben Xu
- Qingqing Xiong
- Yunfei Feng
- Huahua Du
View Affiliations

Affiliations: Key Laboratory of Animal Feed and Nutrition of Zhejiang Province, College of Animal Science, Zhejiang University, Hangzhou, Zhejiang 310058, P.R. China, Key Laboratory of Animal Feed and Nutrition of Zhejiang Province, College of Animal Science, Zhejiang University, Hangzhou, Zhejiang 310058, P.R. China, Department of Endocrinology and Metabolism, The First Affiliated Hospital of Medical School of Zhejiang University, Hangzhou, Zhejiang 310000, P.R. China
Published online on: August 10, 2021 https://doi.org/10.3892/mmr.2021.12352
Article Number: 713
Copyright: © Zhao et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Ferroptosis is a non‑apoptotic form of cell death that relies on iron and lipid peroxidation, which is associated with multiple pathological processes in several diseases. Erastin is a small molecule capable of initiating ferroptotic cell death in cancer cells, which has shown great potential for cancer therapy. However, the physiological and pathological role of erastin‑induced ferroptosis on healthy tissues has not been well characterized. The present study intraperitoneally injected erastin into healthy mice to detect the metabolic changes of several tissues of mice. Erastin injection induced typical characteristics of ferroptosis with higher level of serum iron and malondialdehyde and lower level of glutathione and glutathione peroxidase 4 protein. Erastin injection enhanced iron deposition in the brain, duodenum, kidney and spleen of mice. Erastin‑induced ferroptosis altered the blood index values, causing mild cerebral infarction of brain and enlarged glomerular volume of kidney. It also promoted the growth of duodenal epithelium with thicker, longer and denser villi in erastin‑treated mice. The findings provided evidence that erastin induced ferroptosis and caused pathological changes in healthy tissues of mice. This suggested that the anti‑tumor drug erastin was somewhat toxic to healthy tissues.

View Figures

View References

1	Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, Patel DN, Bauer AJ, Cantley AM, Yang WS, et al: Ferroptosis: An iron-dependent form of nonapoptotic cell death. Cell. 149:1060–1072. 2012. View Article : Google Scholar : PubMed/NCBI
2	Tang D, Kang R, Berghe TV, Vandenabeele P and Kroemer G: The molecular machinery of regulated cell death. Cell Res. 29:347–364. 2019. View Article : Google Scholar : PubMed/NCBI
3	Xie Y, Hou W, Song X, Yu Y, Huang J, Sun X, Kang R and Tang D: Ferroptosis: Process and function. Cell Death Differ. 23:369–379. 2016. View Article : Google Scholar : PubMed/NCBI
4	Yang WS, SriRamaratnam R, Welsch ME, Shimada K, Skouta R, Viswanathan VS, Cheah JH, Clemons PA, Shamji AF, Clish CB, et al: Regulation of ferroptotic cancer cell death by GPX4. Cell. 156:317–331. 2014. View Article : Google Scholar : PubMed/NCBI
5	Xia Y, Sun X, Luo Y and Stary CM: Ferroptosis contributes to isoflurane neurotoxicity. Front Mol Neurosci. 11:4862019. View Article : Google Scholar : PubMed/NCBI
6	Belavgeni A, Meyer C, Stumpf J, Hugo C and Linkermann A: Ferroptosis and necroptosis in the kidneys. Cell Chem Biol. 27:448–462. 2020. View Article : Google Scholar : PubMed/NCBI
7	Yamada N, Karasawa T, Kimura H, Watanabe S, Komada T, Kamata R, Sampilvanjil A, Ito J, Nakagawa K, Kuwata H, et al: Ferroptosis driven by radical oxidation of n-6 polyunsaturated fatty acids mediates acetaminophen-induced acute liver failure. Cell Death Dis. 11:1442020. View Article : Google Scholar : PubMed/NCBI
8	Li Y, Feng D, Wang Z, Zhao Y, Sun R, Tian D, Liu D, Zhang F, Ning S, Yao J and Tian X: Ischemia-induced ACSL4 activation contributes to ferroptosis-mediated tissue injury in intestinal ischemia/reperfusion. Cell Death Differ. 26:2284–2299. 2019. View Article : Google Scholar : PubMed/NCBI
9	Dolma S, Lessnick SL, Hahn WC and Stockwell BR: Identification of genotype-selective antitumor agents using synthetic lethal chemical screening in engineered human tumor cells. Cancer Cell. 3:285–296. 2003. View Article : Google Scholar : PubMed/NCBI
10	Bridges RJ, Natale NR and Patel SA: System xc⁻ cystine/glutamate antiporter: An update on molecular pharmacology and roles within the CNS. Br J Pharmacol. 165:20–34. 2012. View Article : Google Scholar : PubMed/NCBI
11	Forcina GC and Dixon SJ: GPX4 at the crossroads of lipid homeostasis and ferroptosis. Proteomics. 19:e18003112019. View Article : Google Scholar : PubMed/NCBI
12	Xu T, Ding W, Ji X, Ao X, Liu Y, Yu W and Wang J: Molecular mechanisms of ferroptosis and its role in cancer therapy. J Cell Mol Med. 23:4900–4912. 2019. View Article : Google Scholar : PubMed/NCBI
13	Zhao Y, Li Y, Zhang R, Wang F, Wang T and Jiao Y: The role of erastin in ferroptosis and its prospects in cancer therapy. Onco Targets Ther. 13:5429–5441. 2020. View Article : Google Scholar : PubMed/NCBI
14	Huo H, Zhou Z, Qin J, Liu W, Wang B and Gu Y: Erastin disrupts mitochondrial permeability transition pore (mPTP) and induces apoptotic death of colorectal cancer cells. PLoS One. 11:e01546052016. View Article : Google Scholar : PubMed/NCBI
15	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
16	Hambright WS, Fonseca RS, Chen L, Na R and Ran Q: Ablation of ferroptosis regulator glutathione peroxidase 4 in forebrain neurons promotes cognitive impairment and neurodegeneration. Redox Biol. 12:8–17. 2017. View Article : Google Scholar : PubMed/NCBI
17	Sui M, Jiang X, Chen J, Yang H and Zhu Y: Magnesium isoglycyrrhizinate ameliorates liver fibrosis and hepatic stellate cell activation by regulating ferroptosis signaling pathway. Biomed Pharmacother. 106:125–133. 2018. View Article : Google Scholar : PubMed/NCBI
18	Fang X, Wang H, Han D, Xie E, Yang X, Wei J, Gu S, Gao F, Zhu N, Yin X, et al: Ferroptosis as a target for protection against cardiomyopathy. Proc Natl Acad Sci USA. 116:2672–2680. 2019. View Article : Google Scholar : PubMed/NCBI
19	Imai H, Matsuoka M, Kumagai T, Sakamoto T and Koumura T: Lipid peroxidation-dependent cell death regulated by GPx4 and ferroptosis. Curr Top Microbiol Immunol. 403:143–170. 2017.PubMed/NCBI
20	Youssef LA, Rebbaa A, Pampou S, Weisberg SP, Stockwell BR, Hod EA and Spitalnik SL: Increased erythrophagocytosis induces ferroptosis in red pulp macrophages in a mouse model of transfusion. Blood. 131:2581–2593. 2018. View Article : Google Scholar : PubMed/NCBI
21	NaveenKumar SK, SharathBabu BN, Hemshekhar M, Kemparaju K, Girish KS and Mugesh G: The role of reactive oxygen species and ferroptosis in heme-mediated activation of human platelets. ACS Chem Biol. 13:1996–2002. 2018. View Article : Google Scholar : PubMed/NCBI
22	Li X, He T, Yu K, Lu Q, Alkasir R, Guo G and Xue Y: Markers of iron status are associated with risk of hyperuricemia among Chinese adults: Nationwide population-based study. Nutrients. 10:1912018. View Article : Google Scholar : PubMed/NCBI
23	Tuo QZ, Lei P, Jackman KA, Li XL, Xiong H, Li XL, Liuyang ZY, Roisman L, Zhang ST, Ayton S, et al: Tau-mediated iron export prevents ferroptotic damage after ischemic stroke. Mol Psychiatry. 22:1520–1530. 2017. View Article : Google Scholar : PubMed/NCBI
24	Hanninen MM, Haapasalo J, Haapasalo H, Fleming RE, Britton RS, Bacon BR and Parkkila S: Expression of iron-related genes in human brain and brain tumors. BMC Neurosci. 10:362009. View Article : Google Scholar : PubMed/NCBI
25	Xu M, Tao J, Yang Y, Tan S, Liu H, Jiang J, Zheng F and Wu B: Ferroptosis involves in intestinal epithelial cell death in ulcerative colitis. Cell Death Dis. 11:862020. View Article : Google Scholar : PubMed/NCBI
26	Simões F, Ousingsawat J, Wanitchakool P, Fonseca A, Cabrita I, Benedetto R, Schreiber R and Kunzelmann K: CFTR supports cell death through ROS-dependent activation of TMEM16F (anoctamin 6). Pflugers Arch. 470:305–314. 2018. View Article : Google Scholar : PubMed/NCBI
27	Schnabel D, Salas-Vidal E, Narváez V, Sánchez-Carbente Mdel R, Hernández-García D, Cuervo R and Covarrubias L: Expression and regulation of antioxidant enzymes in the developing limb support a function of ROS in interdigital cell death. Dev Biol. 291:291–299. 2006. View Article : Google Scholar : PubMed/NCBI
28	Pu Y, Li S, Xiong H, Zhang X, Wang Y and Du H: Iron promotes intestinal development in neonatal piglets. Nutrients. 10:7262018. View Article : Google Scholar : PubMed/NCBI
29	Park SJ, Cho SS, Kim KM, Yang JH, Kim JH, Jeong EH, Yang JW, Han CY, Ku SK, Cho IJ and Ki SH: Protective effect of sestrin2 against iron overload and ferroptosis-induced liver injury. Toxicol Appl Pharmacol. 379:1146652019. View Article : Google Scholar : PubMed/NCBI
30	Kong Z, Liu R and Cheng Y: Artesunate alleviates liver fibrosis by regulating ferroptosis signaling pathway. Biomed Pharmacother. 109:2043–2053. 2019. View Article : Google Scholar : PubMed/NCBI
31	Tsurusaki S, Tsuchiya Y, Koumura T, Nakasone M, Sakamoto T, Matsuoka M, Imai H, Yuet-Yin Kok C, Okochi H, Nakano H, et al: Hepatic ferroptosis plays an important role as the trigger for initiating inflammation in nonalcoholic steatohepatitis. Cell Death Dis. 10:4492019. View Article : Google Scholar : PubMed/NCBI
32	Li T, Liu X, Jiang L, Manfredi J, Zha S and Gu W: Loss of p53-mediated cell-cycle arrest, senescence and apoptosis promotes genomic instability and premature aging. Oncotarget. 7:11838–11849. 2016. View Article : Google Scholar : PubMed/NCBI