Hypoxia-inducible factor-2α:a novel therapeutic target for intestine-related diseases
10.3867/j.issn.1000-3002.2025.08277
- VernacularTitle:肠道相关疾病治疗新靶点-低氧诱导因子2α
- Author:
Siyu ZHAO
1
;
Qingyu LI
;
Taha REHAM
;
Yan XU
;
Li XIAO
;
Lixin SUN
Author Information
1. 中国药科大学多靶标天然药物全国重点实验室新药筛选与药效评价中心,江苏 南京 210009
- Publication Type:Journal Article
- Keywords:
hypoxia-inducible factor-2α;
iron;
inflammatory bowel disease;
colorectal cancer;
obesity;
targeted modulators
- From:
Chinese Journal of Pharmacology and Toxicology
2025;39(6):469-480
- CountryChina
- Language:Chinese
-
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.
