铁死亡与内质网应激在溃疡性结肠炎病理机制中的研究进展

doi:10.3969/j.issn.1006-5725.2026.04.024

摘要/Abstract

摘要：

溃疡性结肠炎（ulcerative colitis，UC）是一种以结肠黏膜慢性复发性炎症为特征的炎症性肠病，其发病机制涉及黏膜屏障破坏、免疫稳态失衡及多种应激性细胞死亡过程。近年来，铁依赖性脂质过氧化驱动的程序性细胞死亡——铁死亡（ferroptosis），以及以未折叠蛋白反应（unfolded protein response，UPR）为核心的内质网应激（endoplasmic reticulum stress， ERS），被认为在UC发生发展中发挥关键作用。大量研究证实，在UC患者及实验性结肠炎模型中，结肠组织存在铁稳态紊乱、脂质过氧化物蓄积、谷胱甘肽（glutathione，GSH）耗竭及谷胱甘肽过氧化物酶4（glutathione peroxidase 4，GPX4）失活等铁死亡特征；药理或遗传学抑制铁死亡可显著减轻黏膜损伤和炎症反应。与此同时，肠上皮细胞中ERS持续激活，表现为内质网分子伴侣（glucose-regulated protein 78，GRP78）功能耗竭、C/EBP同源蛋白（C/EBP homologous protein，CHOP）和X盒结合蛋白1（X-box binding protein 1，XBP1）信号异常增强，其失衡可直接导致杯状细胞丢失和屏障功能破坏。值得注意的是，铁死亡与ERS并非独立事件，而是在UC炎症微环境中形成相互促进的病理网络：ERS可通过消耗GSH、放大氧化应激而增强铁死亡敏感性；反之，铁死亡产生的大量氧化脂质及损伤相关分子又可反向加重ERS，形成恶性循环。基于此，靶向铁死亡—ERS轴的干预策略，尤其是结合纳米递送系统实现精准调控，正逐渐成为UC治疗研究的重要方向。

关键词: 溃疡性结肠炎, 铁死亡, 内质网应激

Abstract:

Ulcerative colitis （UC） represents a specific manifestation of inflammatory bowel disease， which is distinguished by the chronic and recurrent inflammation of the colonic mucosa. The pathogenesis of UC encompasses the disruption of the intestinal mucosal barrier， the dysregulation of immune homeostasis， and the activation of multiple stress-related cell death pathways. In recent years， mounting evidence has demonstrated that ferroptosis， a type of regulated cell death propelled by iron-dependent lipid peroxidation， and endoplasmic reticulum stress （ERS）， mainly mediated by the unfolded protein response （UPR）， assume crucial roles in the onset and progression of UC. Research has revealed that colonic tissues obtained from patients with UC and experimental colitis models display dysregulated iron homeostasis， the accumulation of lipid peroxides， the depletion of glutathione （GSH）， and the inactivation of glutathione peroxidase 4 （GPX4）， all of which are characteristic hallmarks of ferroptosis. It has been reported that pharmacological or genetic inhibition of ferroptosis can mitigate mucosal injury and inflammatory responses. Meanwhile， the persistent activation of ERS in intestinal epithelial cells is evident， as indicated by the functional exhaustion of the endoplasmic reticulum chaperone glucose - regulated protein 78 （GRP78） and the enhanced signaling of C/EBP homologous protein （CHOP） and X-box binding protein 1 （XBP1）. Dysregulated ERS can directly lead to goblet cell loss and the impairment of epithelial barrier function. Significantly， ferroptosis and ERS are not independent processes but interact with each other within the inflammatory microenvironment of UC. ERS can enhance cellular susceptibility to ferroptosis by depleting GSH and intensifying oxidative stress. Conversely， excessive lipid peroxides and damage-associated molecular patterns produced during ferroptosis may further exacerbate ERS， thus forming a detrimental feedback loop. Therefore， therapeutic strategies targeting the ferroptosis-ERS axis， especially those integrated with nanotechnology-based delivery systems for precise regulation， might represent a promising approach for the treatment of UC.

Key words: ulcerative colitis, ferroptosis, endoplasmic reticulum stress

中图分类号:

R574.62

肖仟骏,崔春晖. 铁死亡与内质网应激在溃疡性结肠炎病理机制中的研究进展[J]. 实用医学杂志, 2026, 42(4): 714-722.

Qianjun XIAO,Chunhui CUI. Advances in the study of ferroptosis and endoplasmic reticulum stress in the pathological mechanisms of ulcerative colitis[J]. The Journal of Practical Medicine, 2026, 42(4): 714-722.

图/表 6

图1

图2

图3

图4

图5

图6

参考文献 40

[1]	XU J， LIU S， CUI Z， et al. Ferrostatin-1 alleviated TNBS induced colitis via the inhibition of ferroptosis［J］. Biochem Biophys Res Commun， 2021， 573： 48-54. doi：10.1016/j.bbrc. 2021.08.018 . doi: 10.1016/j.bbrc. 2021.08.018
[2]	KASER A， LEE A H， FRANKE A， et al. XBP1 links ER stress to intestinal inflammation and confers genetic risk for human inflammatory bowel disease［J］. Cell， 2008， 134（5）： 743-756. doi：10.1016/j.cell.2008.07.021 . doi: 10.1016/j.cell.2008.07.021
[3]	ZHANG H-S， CHEN Y， FAN L， et al. The endoplasmic reticulum stress sensor IRE1α in intestinal epithelial cells is essential for protecting against colitis［J］. J Biol Chem， 2015， 290（24）： 15327-15336. doi：10.1074/jbc.M114.633560 . doi: 10.1074/jbc.M114.633560
[4]	DONG H， DU W， DONG J， et al. Depletable peroxidase-like activity of Fe3O4 nanozymes accompanied with separate migration of electrons and iron ions［J］. Nat Commun， 2022， 13（1）：5365. doi：10.1038/s41467-022-33098-y . doi: 10.1038/s41467-022-33098-y
[5]	HONG Y， BOITI A， VALLONE D， et al. Reactive oxygen species signaling and oxidative stress： Transcriptional regulation and evolution［J］. Antioxidants， 2024， 13（3）： 312. doi：10.3390/antiox13030312 . doi: 10.3390/antiox13030312
[6]	CUI X， ZHANG Y， LU Y， et al. ROS and endoplasmic reticulum stress in pulmonary disease［J］. Front Pharmacol， 2022， 13： 879204. doi：10.3389/fphar.2022.879204 . doi: 10.3389/fphar.2022.879204
[7]	DIXON S J， LEMBERG K M， LAMPRECHT M R， et al. Ferroptosis： An iron-dependent form of nonapoptotic cell death［J］. Cell， 2012， 149（5）： 1060-1072. doi：10.1016/j.cell. 2012. 03.042 . doi: 10.1016/j.cell. 2012. 03.042
[8]	STOCKWELL B R， JIANG X， GU W， et al. Emerging mechanisms and disease relevance of ferroptosis［J］. Trends Cell Biol， 2020， 30（6）： 478-490. doi：10.1016/j.tcb.2020.02.009 . doi: 10.1016/j.tcb.2020.02.009
[9]	FRIEDMANN ANGELI J P， SCHNEIDER M， PRONETH B， et al. Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice［J］. Nat Cell Biol， 2014， 16（12）： 1180-1191. doi：10.1038/ncb3064 . doi: 10.1038/ncb3064
[10]	MURPHY M E. Ironing out how P53 regulates ferroptosis［J］. Proc Natl Acad Sci U S A， 2016， 113（44）： 12350-12352. doi：10.1073/pnas.1615159113 . doi: 10.1073/pnas.1615159113
[11]	HUANG J， ZHANG J， MA J， et al. Inhibiting ferroptosis： A novel approach for ulcerative colitis therapeutics［J］. Oxid Med Cell Longev， 2022， 2022：9678625. doi：10.1155/2022/9678625 . doi: 10.1155/2022/9678625
[12]	XIE H， CAO C， SHU D， et al. The important role of ferroptosis in inflammatory bowel disease［J］. Front Med， 2024， 11： 1449037. doi：10.3389/fmed.2024.1449037 . doi: 10.3389/fmed.2024.1449037
[13]	XU M， TAO J， YANG Y， et al. Ferroptosis involves in intestinal epithelial cell death in ulcerative colitis［J］. Cell Death Dis， 2020， 11（2）：86. doi：10.1038/s41419-020-2299-1 . doi: 10.1038/s41419-020-2299-1
[14]	LI X， HE J， GAO X， et al. GPX4 restricts ferroptosis of NKp46+ ILC3s to control intestinal inflammation［J］. Cell Death Dis， 2024， 15（9）：687. doi：10.1038/s41419-024-07060-3 . doi: 10.1038/s41419-024-07060-3
[15]	CHEN H， QIAN Y， JIANG C， et al. Butyrate ameliorated ferroptosis in ulcerative colitis through modulating Nrf2/GPX4 signal pathway and improving intestinal barrier［J］. Biochim Biophys Acta Mol Basis Dis， 2024， 1870（2）： 166984. doi：10.1016/j.bbadis.2023.166984 . doi: 10.1016/j.bbadis.2023.166984
[16]	ZHENG S， YIN J， WANG B， et al. Polydatin protects against DSS-induced ulcerative colitis via Nrf2/Slc7a11/Gpx4-dependent inhibition of ferroptosis signalling activation［J］. Front Pharmacol， 2025， 15：1513020. doi：10.3389/fphar.2024.1513020 . doi: 10.3389/fphar.2024.1513020
[17]	HETZ C， PAPA F R. The unfolded protein response and cell fate control［J］. Mol Cell， 2018， 69（2）： 169-181. doi：10.1016/j.molcel.2017.06.017 . doi: 10.1016/j.molcel.2017.06.017
[18]	COLEMAN O I， HALLER D， et al. ER stress and the UPR in shaping intestinal tissue homeostasis and immunity［J］. Front Immunol， 2019， 10：2825. doi：10.3389/fimmu.2019.02825 . doi: 10.3389/fimmu.2019.02825
[19]	RODRIGUES B L， DOTTI I， PASCOAL L B， et al. Endoplasmic reticulum stress in colonic mucosa of ulcerative colitis patients is mediated by PERK and IRE1 pathway activation［J］. Mediators Inflamm， 2022， 2022： 1-13. doi：10.1155/2022/6049500 . doi: 10.1155/2022/6049500
[20]	TRÉTON X， PÉDRUZZI E， CAZALS-HATEM D， et al. Altered endoplasmic reticulum stress affects translation in inactive colon tissue from patients with ulcerative colitis［J］. Gastroenterology， 2011， 141（3）： 1024-1035. doi：10.1053/j.gastro.2011.05.033 . doi: 10.1053/j.gastro.2011.05.033
[21]	JEONG H， HONG E H， AHN J H， et al. ERdj5 protects goblet cells from endoplasmic reticulum stress-mediated apoptosis under inflammatory conditions［J］. Exp Mol Med， 2023， 55（2）： 401-412. doi：10.1038/s12276-023-00945-x . doi: 10.1038/s12276-023-00945-x
[22]	WANG Y， HAO Y， YUAN L， et al. Ferroptosis： A new mechanism of traditional Chinese medicine for treating ulcerative colitis［J］. Front Pharmacol， 2024， 15：1379058. doi：10.3389/fphar. 2024.1379058 . doi: 10.3389/fphar. 2024.1379058
[23]	OCANSEY D， YUAN J， WEI Z， et al. Role of ferroptosis in the pathogenesis and as a therapeutic target of inflammatory bowel disease （review）［J］. Int J Mol Med， 2023， 51（6）：53. doi：10.3892/ijmm.2023.5256 . doi: 10.3892/ijmm.2023.5256
[24]	FAN X， LU Q， JIA Q， et al. Prevotella histicola ameliorates DSS-induced colitis by inhibiting IRE1α-JNK pathway of ER stress and NF-κB signaling［J］. Int Immunopharmacol， 2024， 135： 112285. doi：10.1016/j.intimp.2024.112285 . doi: 10.1016/j.intimp.2024.112285
[25]	URANO F， WANG X， BERTOLOTTI A， et al. Coupling of stress in the ER to activation of JNK protein kinases by transmembrane protein kinase IRE1［J］. Science， 2000， 287（5453）： 664-666. doi：10.1126/science.287.5453.664 . doi: 10.1126/science.287.5453.664
[26]	YANG J， WANG Y， LIU F， et al. Crosstalk between ferroptosis and endoplasmic reticulum stress： A potential target for ovarian cancer therapy （review）［J］. Int J Mol Med， 2025， 55（6）： 1-20. doi：10.3892/ijmm.2025.5538 . doi: 10.3892/ijmm.2025.5538
[27]	HUO C， LI G， HU Y， et al. The impacts of iron overload and ferroptosis on intestinal mucosal homeostasis and inflammation［J］. Int J Mol Sci， 2022， 23（22）： 14195. doi：10.3390/ijms 232214195 . doi: 10.3390/ijms 232214195
[28]	YAO T， DONG X， LV J， et al. Propionate alleviated colitis by modulating iron homeostasis to inhibit ferroptosis and macrophage polarization［J］. Int Immunopharmacol， 2025， 162： 115151. doi：10.1016/j.intimp.2025.115151 . doi: 10.1016/j.intimp.2025.115151
[29]	MINOR E A， KUPEC J T， NICKERSON A J， et al. Increased DMT1 and FPN1 expression with enhanced iron absorption in ulcerative colitis human colon［J］. Am J Physiol Cell Physiol， 2020， 318（2）： C263-C271. doi：10.1152/ajpcell.00128.2019 . doi: 10.1152/ajpcell.00128.2019
[30]	LIU Z， ARCOS M， MARTIN D R， et al. Myeloid FTH1 deficiency protects mice from colitis and colitis-associated colorectal cancer via reducing DMT1-imported iron and STAT3 activation［J］. Inflamm Bowel Dis， 2023， 29（8）： 1285-1296. doi：10.1093/ibd/izad009 . doi: 10.1093/ibd/izad009
[31]	CHEN Y， ZHANG P， CHEN W， et al. Ferroptosis mediated DSS-induced ulcerative colitis associated with Nrf2/HO-1 signaling pathway［J］. Immunol Lett， 2020， 225： 9-15. doi：10.1016/j.imlet.2020.06.005 . doi: 10.1016/j.imlet.2020.06.005
[32]	GUO Z， CHI R， PENG Y， et al. The role and interactive mechanism of endoplasmic reticulum stress and ferroptosis in musculoskeletal disorders［J］. Biomolecules， 2024， 14（11）： 1369. doi：10.3390/biom14111369 . doi: 10.3390/biom14111369
[33]	GU K， WU A， YU B， et al. Iron overload induces colitis by modulating ferroptosis and interfering gut microbiota in mice［J］. Sci Total Environ， 2023， 905： 167043. doi：10.1016/j.scitotenv.2023.167043 . doi: 10.1016/j.scitotenv.2023.167043
[34]	SUN J， WANG Y， DU Y， et al. Involvement of the JNK/HO-1/FTH1 signaling pathway in nanoplastic-induced inflammation and ferroptosis of BV2 microglia cells［J］. Int J Mol Med， 2023， 52（1）. doi：10.3892/ijmm.2023.5264 . doi: 10.3892/ijmm.2023.5264
[35]	CHEN H， SUN W， LI C， et al. Inflammatory targeted nanoplatform incorporated with antioxidative nano iron oxide to attenuate ulcerative colitis progression［J］. iScience， 2025， 28（5）： 112448. doi：10.1016/j.isci.2025.112448 . doi: 10.1016/j.isci.2025.112448
[36]	FENG Y， LUO X， LI Z， et al. A ferroptosis-targeting ceria anchored halloysite as orally drug delivery system for radiation colitis therapy［J］. Nat Commun， 2023， 14（1）：5083. doi：10.1038/s41467-023-40794-w . doi: 10.1038/s41467-023-40794-w
[37]	WANG H， LIU Y， HUANG R， et al. Oral HMPB/Mn3O4 nanozymes for the treatment of ulcerative colitis via cellular redox balance regulation， gut microbiota modulation， and ferroptosis inhibition［J］. Chem Eng J， 2025， 519： 165265. doi：10.1016/j.cej.2025.165265 . doi: 10.1016/j.cej.2025.165265
[38]	FAN S， ZHAO Y， YAO Y， et al. Oral colon-targeted pH-responsive polymeric nanoparticles loading naringin for enhanced ulcerative colitis therapy［J］. J Transl Med， 2024， 22（1）：878. doi：10.1186/s12967-024-05662-1 . doi: 10.1186/s12967-024-05662-1
[39]	SHI J， ZHOU J， LIU B， et al. Enzyme/ROS dual-sensitive nanoplatform with on-demand celastrol release capacity for enhanced ulcerative colitis therapy by ROS scavenging， microbiota rebalancing， inflammation alleviating［J］. J Nanobiotechnol， 2024， 22（1）：437. doi：10.1186/s12951-024-02725-9 . doi: 10.1186/s12951-024-02725-9
[40]	ZHOU J， LU P， HE H， et al. The metabolites of gut microbiota： their role in ferroptosis in inflammatory bowel disease［J］. Eur J Med Res， 2025， 30（1）：248. doi：10.1186/s40001-025-02524-4 . doi: 10.1186/s40001-025-02524-4