摘要
处于生理性缺氧状态的肠道是机体的重要器官,其主要功能是消化、吸收和排泄及分泌激素、提供屏障和免疫保护等。低氧诱导因子2α(HIF-2α)是肠道重要的生理调节因子,其在肠道内环境铁稳态、氧稳态及能量代谢等调节中发挥重要作用。近期研究表明,HIF-2α与铁相关血液性疾病、炎症性肠病(IBD)、结直肠癌(CRC)及肥胖相关代谢性疾病等多种肠道相关疾病的发生和进展密切相关,可能是其治疗新靶点。目前,HIF-2α调节剂是此领域药物研发的热点,大量研究揭示其具有肠道相关疾病治疗潜力。HIF-2α是肠道铁吸收与铁稳态的关键调控因子,其表达异常与多种铁代谢紊乱性血液系统疾病密切相关。在肠道病理性缺氧微环境下,HIF-2α的持续激活可诱导炎症反应和上皮屏障功能障碍,从而加重IBD病情。在肿瘤微环境中,HIF-2α通过介导代谢重编程、促进血管新生、增强肿瘤细胞的增殖、迁移与侵袭能力,同时驱动炎症反应、铁蓄积及免疫逃逸等,加速CRC进展。此外,HIF-2α还可通过肠-肝轴参与肥胖、胰岛素抵抗及糖脂代谢的调节。尽管目前已有7种HIF-2α调节剂获批上市,但其在临床应用中仍存在贫血、血栓等不良反应。因此,开发更加低毒高效的HIF-2α调节策略,将是未来研究的重要方向。本文总结近年来HIF-2α在肠道健康和相关疾病中的作用及机制,分析未来HIF-2α调节剂在研发和应用方面的挑战,以期为肠道相关疾病治疗提供新方案。
The intestine in a hypoxic state is an essential physiological organ,and its primary func-tions include digestion,absorption,excretion,hormone secretion,and providing barrier and immune protec-tion.Hypoxia-inducible factor-2α(HIF-2α)represents one of the important physiologicalregulators for the intestine,partaking in the regulation of iron homeostasis,oxygen homeostasis and energy metabo-lism in the intestinal environment.Recent studies have shown that HIF-2αis closely associated with the onset and progression of various intestinal-related diseases,including iron-relatedblood diseases,inflam-matory bowel disease(IBD),colorectal cancer(CRC),and obesity-related metabolic diseases.Thus,HIF-2αmay be a novel target for the treatment.HIF-2αis currently a hot topic in drug development,and numerous studies have revealed that it has therapeutic potential for intestinal-related diseases.HIF-2αis a key transcription factor that regulates intestinal iron absorption and systemic iron homeostasis.Aberrant expression of HIF-2αhas been closely linked to various hematological disorders associated with iron metabolism dysregulation.In the pathological hypoxic microenvironment of the intestine,sustained activation of HIF-2αinduces inflammatory response and impairs epithelial barrier function,thereby exacerbating the progression of IBD.Within the tumor microenvironment,HIF-2αcontributes to CRC progression through multiple mechanisms,including metabolic reprogramming,angiogenesis,enhanced prolifera-tion,migration,and invasion of tumor cells,as well as inflammation,iron accumulation,and immune evasion.Moreover,HIF-2αis involved in the regulation of obesity,insulin resistance,and glucose-lipid metabolism via the gut-liver axis.Although seven HIF-2αmodulators have been approved for clinical use,adverse effects such as anemia and thrombosis remain concerns.Therefore,developing next-generation HIF-2α-targeted strategies with improved specificity and safety profiles is critical to future research.This article is an overview of the recent advancements in understanding the role and mecha-nisms of HIF-2αin intestinal health and associated diseases while analyzing the challenges to develop-ment and application of HIF-2αmodulators in the future,in hopes of offering novel therapeutic avenues for intestinal-related ailments.
作者
赵思羽
李清钰
Reham Taha
徐艳
肖莉
孙丽新
ZHAO Siyu;LI Qingyu;Reham Taha;XU Yan;XIAO Li;SUN Lixin(New Drug Screening and Pharmacodynamics Evaluation Center,State Key Laboratory of Natural Medicines,China Pharmaceutical University,Nanjing 210009,China;Key Laboratory of Vector Biology and Pathogen Control of Zhejiang Province,College of Life Sciences,Huzhou University,Huzhou 313000,China)
出处
《中国药理学与毒理学杂志》
北大核心
2025年第6期469-480,共12页
Chinese Journal of Pharmacology and Toxicology
基金
国家自然科学基金(82074115)
浙江省基础公益研究计划(LGN21C020002)。
关键词
低氧诱导因子2α
铁
炎症性肠病
结直肠癌
肥胖
靶向调节剂
hypoxia-inducible factor-2α
iron
inflammatory bowel disease
colorectal cancer
obesity
targeted modulators
