中国药理学与毒理学杂志2025，Vol.39Issue(6)：469-480,12.DOI:10.3867/j.issn.1000-3002.2025.08277
肠道相关疾病治疗新靶点-低氧诱导因子2α
Hypoxia-inducible factor-2α:a novel therapeutic target for intestine-related diseases
摘要
Abstract
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-2α is 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-2α may be a novel target for the treatment.HIF-2α is currently a hot topic in drug development,and numerous studies have revealed that it has therapeutic potential for intestinal-related diseases.HIF-2α is a key transcription factor that regulates intestinal iron absorption and systemic iron homeostasis.Aberrant expression of HIF-2α has been closely linked to various hematological disorders associated with iron metabolism dysregulation.In the pathological hypoxic microenvironment of the intestine,sustained activation of HIF-2α induces inflammatory response and impairs epithelial barrier function,thereby exacerbating the progression of IBD.Within the tumor microenvironment,HIF-2α contributes 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-2α is involved in the regulation of obesity,insulin resistance,and glucose-lipid metabolism via the gut-liver axis.Although seven HIF-2α modulators 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-2α in intestinal health and associated diseases while analyzing the challenges to develop-ment and application of HIF-2α modulators in the future,in hopes of offering novel therapeutic avenues for intestinal-related ailments.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Key words
hypoxia-inducible factor-2α/iron/inflammatory bowel disease/colorectal cancer/obesity/targeted modulators分类
医药卫生引用本文复制引用
赵思羽,李清钰,Reham Taha,徐艳,肖莉,孙丽新..肠道相关疾病治疗新靶点-低氧诱导因子2α[J].中国药理学与毒理学杂志,2025,39(6):469-480,12.基金项目
国家自然科学基金(82074115) （82074115）
浙江省基础公益研究计划(LGN21C020002) National Natural Science Foundation of China(82074115) （LGN21C020002）
and Zhejiang Provincial Basic Public Welfare Research Program(LGN21C020002) （LGN21C020002）
