摘要：肾细胞癌 （renal cell carcinoma，RCC） 是最常见的的泌尿系统恶性肿瘤之一。铁死亡是一种与铁依赖相 关新型细胞凋亡方式，受多种细胞代谢的调节，包括氧化还原稳态、铁吸收、线粒体活性和氨基酸、脂质和糖的代谢等。铁死亡与肾癌的发生发展密切相关，铁死亡相关基因可以导致细胞膜不饱和脂肪酸发生氧化，进而引起 细胞凋亡，一些铁死亡基因可作为肾癌早期诊断的潜在生物标志物。本文就铁死亡在肾癌中的作用机制及早期诊 断相关生物学标志物做一综述。

暂无相关信息！

[1] WANG B, SONG Q, WEI Y, et al. Comprehensive investigation into cuproptosis in the characterization of clinical features molecular characteristics, and immune situations of clear cell renal cell carcinoma [J]. Front Immunol, 2022, 13: 948042

[2] KAELIN WG JR. The von Hippel- Lindau tumour suppressor protein: O2 sensing and cancer [J]. NatRev Cancer, 2008, 8(11): 865-873

[3] SCHRÖDTER S, BRAUN M, SYRING I, et al. Identification of the dopamine transporter SLC6A3 as a biomarker for patients with renal cell carcinoma [J]. MolCancer, 2016, 15: 10

[4] LOBO J, OHASHI R, AMIN MB, et al. WHO 2022 landscape of papillary and chromophobe renal cell carcinoma [J]. Histopathology, 2022, 81(4): 426-438

[5] ATKINS MB, TANNIR NM. Current and emerging therapies for first- line treatment of metastatic clear cell renal cell carcinoma [J]. Cancer TreatRev, 2018, 70: 127- 137

[6] LIU J, KUANG F, KROEMER G, et al. AutophagyDependent Ferroptosis: Machinery and Regulation [J]. Cell ChemBiol,2020, 27(4): 420-435

[7] CHEN X, YU C, KANG R, et al. Cellular degradation systems in ferroptosis [J]. Cell Death Differ, 2021, 28(4): 1135-1148

[8] YANG WS, STOCKWELL BR. Ferroptosis: Death by Lipid Peroxidation [J]. Trends in cell biology, 2016, 26(3): 165-176

[9] DIXON SJ, LEMBERG KM, LAMPRECHT MR, et al. Ferroptosis: an iron- dependent form of nonapoptotic cell death [J]. Cell,2012, 149(5): 1060-1072

[10] JIANG N, ZHANG X, GU X, et al. Progress in understanding the role of lncRNA in programmed cell death [J]. Cell Death Discov, 2021, 7(1):30

[11] GALLUZZI L, VITALE I, ABRAMS JM, et al. Molecular definitions of cell death subroutines: recommendations of the Nomenclature Committee on Cell Death 2012 [J]. Cell Death Differ, 2012, 19(1): 107-120

[12] GAO M, MONIAN P, PAN Q, et al. Ferroptosis is an autophagic cell death process [J]. Cell Rese, 2016, 26(9): 1021-1032

[13] GENG N, SHI BJ, LI SL, et al. Knockdown of ferroportin accelerates erastin- induced ferroptosis in neuroblastoma cells [J]. Eur Rev Med Pharmacol Sci, 2018, 22(12): 3826- 3836

[14] HOU W, XIE Y, SONG X, et al. Autophagy promotes ferroptosis by degradation of ferritin [J]. Autophagy, 2016, 12(8): 1425-1428

[15] TSOI J, ROBERT L, PARAISO K, et al. Multi- stage Differentiation Defines Melanoma Subtypes with Differential Vulnerability to Drug- Induced Iron- Dependent Oxidative Stress [J]. Cancer Cell, 2018, 33(5): 890-904.e5

[16] HANGAUER MJ, VISWANATHAN VS, RYAN MJ, et al. Drug-tolerant persister cancer cells are vulnerable to GPX4 inhibition [J]. Nature, 2017, 551(7679): 247-250

[17] BROWN CW, AMANTE JJ, GOEL HL, et al. The α6β 4 integrin promotes resistance to ferroptosis [J]. J Cell Biol, 2017, 216(12): 4287-4297

[18] VISWANATHAN VS, RYAN MJ, DHRUV HD, et al. Dependency of a therapy- resistant state of cancer cells on a lipid peroxidase pathway [J]. Nature, 2017, 547(7664): 453-457

[19] TORTI SV, TORTI FM. Iron and cancer: more ore to be mined [J]. NatRev Cancer, 2013, 13(5): 342-355

[20] MANZ DH, BLANCHETTE NL, PAUL BT, et al. Iron and cancer: recent insights [J]. Ann NYAcad Sci, 2016, 1368(1): 149-161

[21] TANG D, CHEN X, KANG R, et al. Ferroptosis: molecular mechanisms and health implications [J]. Cell Res, 2021, 31(2): 107-125

[22] DISTÉFANO AM, MARTIN MV, CÓRDOBA JP, et al. Heat stress induces ferroptosis- like cell death in plants [J]. J Cell Biol, 2017, 216(2): 463-476

[23] HASSANNIA B, VANDENABEELE P, VANDEN BERGHE T. Targeting Ferroptosis to Iron Out Cancer [J]. Cancer Cell, 2019, 35(6): 830-849

[24] SATO H, FUJIWARA K, SAGARA J, et al. Induction of cystine transport activity in mouse peritoneal macrophages by bacterial lipopolysaccharide [J]. Biochem J, 1995, 310(Pt 2):547-551

[25] GREEN DR. The Coming Decade of Cell Death Research: Five Riddles [J]. Cell, 2019, 177(5): 1094-1107

[26] WANG W, GREEN M, CHOI JE, et al. CD8(+) T cells regulate tumour ferroptosis during cancer immunotherapy [J]. Nature, 2019, 569(7755): 270-274

[27] SCHNURR K, BORCHERT A, KUHN H. Inverse regulation of lipid- peroxidizing and hydroperoxyl lipidreducing enzymes by interleukins 4 and 13 [J]. FASEB J, 1999, 13(1): 143-154

[28] PRONETH B, CONRAD M. Ferroptosis and necroinflammation, a yet poorly explored link [J]. Cell Death Differ, 2019, 26(1): 14-24

[29] YANG WS, SRIRAMARATNAM R, WELSCH ME, et al. Regulation of ferroptotic cancer cell death by GPX4 [J]. Cell, 2014, 156(1-2): 317-331

[30] BRIGELIUS- FLOHÉ R, MAIORINO M. Glutathione peroxidases [J]. BiochimBiophys Acta, 2013, 1830(5): 3289- 3303

[31] BASU A, BODYCOMBE NE, CHEAH JH, et al. An interactive resource to identify cancer genetic and lineage dependencies targeted by small molecules [J]. Cell, 2013, 154(5): 1151-1161

[32] DOLMA S, LESSNICK SL, HAHN WC, et al. Identification of genotype- selective antitumor agents using synthetic lethal chemical screening in engineered human tumor cells [J]. Cancer Cell, 2003, 3(3): 285-296

[33] PENALOZA C, LIN L, LOCKSHIN RA, et al. Cell death in development: shaping the embryo [J]. Histochem Cell Biol,2006, 126(2): 149-158

[34] LU Y, QIN H, JIANG B, et al. KLF2 inhibits cancer cell migration and invasion by regulating ferroptosis through GPX4 in clear cell renal cell carcinoma [J]. Cancer Lett, 2021, 522: 1-13

[35] RANE MJ, ZHAO Y, CAI L. Krϋppel- like factors (KLFs) in renal physiology and disease [J]. EBioMedicine, 2019, 40:743-750

[36] SEIBT TM, PRONETH B, CONRAD M. Role of GPX4 in ferroptosis and its pharmacological implication [J]. Free RadicBiol Med, 2019, 133: 144-152

[37] ZHENG Q, LI P, ZHOU X, et al. Deficiency of the X-inactivation escaping gene KDM5C in clear cell renal cell carcinoma promotes tumorigenicity by reprogramming glycogen metabolism and inhibiting ferroptosis [J]. Theranostics, 2021, 11(18): 8674-8691

[38] CHANG S, YIM S, PARK H. The cancer driver genes IDH1/2, JARID1C/ KDM5C, and UTX/ KDM6A: crosstalk between histone demethylation and hypoxic reprogramming in cancer metabolism [J]. Exp Mol Med, 2019, 51(6): 1-17

[39] NIU X, ZHANG T, LIAO L, et al. The von HippelLindau tumor suppressor protein regulates gene expression and tumor growth through histone demethylase JARID1C [J]. Oncogene, 2012, 31(6): 776-786

[40] ZHANG Y, LI Y, QIU Q, et al. MITD1 Deficiency Suppresses Clear Cell Renal Cell Carcinoma Growth and Migration by Inducing Ferroptosis through the TAZ/SLC7A11 Pathway [J]. Oxid Med Cell Longev, 2022, 2022: 7560569

[41] AGROMAYOR M, MARTIN- SERRANO J. Knowing when to cut and run: mechanisms that control cytokinetic abscission [J]. Trends Cell Biol, 2013, 23(9): 433-441

[42] HAN S, LIN F, QI Y, et al. HO- 1 Contributes to Luteolin- Triggered Ferroptosis in Clear Cell Renal Cell Carcinoma via Increasing the Labile Iron Pool and Promoting Lipid Peroxidation [J]. Oxid Med Cell Longev, 2022, 2022: 3846217

[43] CHIANG SK, CHEN SE, CHANG LC. A Dual Role of Heme Oxygenase- 1 in Cancer Cells [J]. Int J Mol Sci, 2018, 20(1): 39

[44] FANG X, WANG H, HAN D, et al. Ferroptosis as a target for protection against cardiomyopathy [J]. Proc Natl Acad Sci U S A, 2019, 116(7): 2672-2680

[45] DONG H, QIANG Z, CHAI D, et al. Nrf2 inhibits ferroptosis and protects against acute lung injury due to intestinal ischemia reperfusion via regulating SLC7A11 and HO-1 [J]. Aging, 2020, 12(13): 12943-12959

[46] GREEN YS, FERREIRA DOS SANTOS MC, FUJA DG, et al. ISCA2 inhibition decreases HIF and induces ferroptosis in clear cell renal carcinoma [J]. Oncogene, 2022, 41(42): 4709-4723

[47] JONASCH E, WALKER CL, RATHMELL WK. Clear cell renal cell carcinoma ontogeny and mechanisms of lethality [J]. Nat Rev Nephrol, 2021, 17(4): 245-261

[48] XIE Y, HOU W, SONG X, et al. Ferroptosis: process and function [J]. Cell Death Differ, 2016, 23(3): 369-379

[49] STOCKWELL BR, FRIEDMANN ANGELI JP, BAYIR H, et al. Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease [J]. Cell, 2017, 171(2): 273-285

[50] WANG W, ZHANG J, WANG Y, et al. Identifies microtubulebinding protein CSPP1 as a novel cancer biomarker associated with ferroptosis and tumor microenvironment [J]. Comput Struct Biotechnol J, 2022, 20: 3322-3335

[51] HUANG R, ZHANG C, WANG X, et al. Identification of FDFT1 as a potential biomarker associated with ferroptosis in ccRCC [J]. Cancer Med, 2022, 11(21): 3993-4004.

高瀚 ，夏庆华.铁死亡基因在肾癌中的研究进展[J]. 泌尿外科杂志（电子版）,2023,15(1):76-81. DOI:10.20020/j.CNKI.1674-7410.2023.01.14

暂无相关信息！

肾癌是泌尿系统最常见的恶性肿瘤之一[1] 。在过 去的几十年里，其发病率在世界范围内呈上升趋势， 仅 2020 年，全球范围内肾癌新确诊人数就超过了 40 万例，其中死亡人数约 20万例，占全球所有确诊 癌症人数的2.4%[2-4] 。肾癌诊断目前依赖临床症状、影 像学及病理改变，缺乏早期诊断标志物。近年来，铁 死亡基因逐渐进入大众视野，研究表明，铁死亡基因 参与肾癌的发生发展，并有早期诊断的潜力[5] 。

铁死亡是近年来发现的一种新型细胞死亡方式， 研究表明，在细胞死亡过程中通常伴有大量铁元素 积累和脂质过氧化反应[6-7] 。铁死亡的发生是铁依赖 性的，铁死亡相关诱导因子可通过不同途径直接或 间接影响谷胱甘肽过氧化物酶的生物活性，导致机 体抗氧化能力下降以及细胞中脂质活性氧 （reactive oxygen species，ROS） 的积累，最终导致细胞氧化 死亡[8-9] 。铁死亡与许多疾病的病理生理过程存在密 切关系，如肿瘤、神经系统疾病、缺血再灌注损 伤、肾损伤和血液疾病等[10-11] 。所以，探索如何通过v> 调节细胞铁死亡过程来干预相关疾病的发生发展已 成为疾病研究和治疗的热点。铁死亡在细胞形态和 功能上与坏死、凋亡、自噬存在明显不同，它不具 有典型细胞坏死的形态学特征，如细胞质和细胞器 的肿胀和细胞膜的破裂，也不具有传统细胞凋亡的 特征，如细胞收缩、染色质凝结、凋亡小体的形成 和细胞骨架的分解[12-14] 。与细胞自噬相反，铁死亡没 有形成经典的封闭双层膜结构。形态学上，铁死亡 主要表现为线粒体明显萎缩，膜密度增加，线粒体 嵴减少或消失，这是与其他细胞死亡模式不同的过程。

关于铁死亡机制研究表明，许多癌症相关基因 和信号通路可以调节铁死亡，进一步研究观察到间 充质干细胞和去分化癌细胞以及筛选的耐药癌细胞 对铁死亡诱导剂均有高度敏感[15-18] ，进一步证实了铁 死亡诱导可以作为一种新型癌症疗法的可能。由于 铁死亡是一种氧化应激诱导的脂质代谢形式的细胞 死亡，因此提出癌细胞可能具有更强烈的铁死亡倾 向似乎也是合乎逻辑的，因为肿瘤细胞具有更加活 跃的新陈代谢和更高的 ROS负荷。除此之外，已经 表明癌细胞有更高的铁元素需求量[19-20] ，这可能使他 们对铁死亡更加敏感。并且铁死亡在癌症中的作用 也取决于其特定的遗传背景。

肾透明细胞癌 （clear cell renal cell carcinoma， ccRCC） 细胞对谷氨酰胺和胱氨酸的消耗有高度敏 感性，谷氨酰胺和胱氨酸是谷胱甘肽 （glutathione， GSH） 合成所必需的成分。机体通过 GSH/谷胱甘 肽过氧化物酶 （glutathione peroxidase，GPX） 途径 来防止脂质过氧化和细胞死亡。研究证实，抑制 ccRCC 中 GSH 合成可诱导铁死亡并抑制肿瘤的生 长，这为肾癌中铁死亡的研究提供了依据。

1 胱氨酸-GSH-GPX4 轴与肾癌

2 肾癌中铁死亡相关标志物的研究

    2.1 GPX4 基因与肾癌

    2.2 KDM5C 基 因 与 肾 癌

    2.3 MITD1 基因与肾癌

    2.4 HO-1基因与肾癌

    2.5 ISCA2 基因与肾癌

    2.6 CSPP1 基因与肾癌

    2.7 FDFT1 基因与肾癌

3 总结与展望

3 总结与展望

铁死亡是一种与铁元素含量或活性氧相关的细 胞死亡过程，参与多种生物过程，与肿瘤的发生发 展密切相关。铁死亡过程可以通过多种药物调节， 铁死亡在肾癌的发生发展中起关键作用，在肾癌中 的研究有可能筛选出新的阻断肾癌进程的靶点，通 过诱导和抑制铁死亡过程对肾癌进行早期干预，对 肾癌患者的治疗有一定的指导意义。随着研究的深 入，铁死亡在越来越多的疾病的病理生理过程中被 发现，也为治疗这些疾病提供了新的思路。此外， 铁死亡作为一种独立的细胞死亡方式，也可以与其 他类型的细胞死亡一起在疾病中发挥作用，这为联 合应用现有治疗方案提供了可能性，有助于解决某 些疾病的耐药性问题。然而，铁死亡的研究仍处于 起步阶段，许多问题仍未解决。但这并不阻碍一些 铁死亡基因有为肾癌早期诊断的生物学标志物，总 的来说，铁死亡相关基因在肾癌的研究中有广阔的 临床应用前景。

暂无相关信息！

暂无相关信息！