pcij-2663-1785781018 20260803181658 PCIJ bmpublisher@bmpublisher.net Pathophysiology of Cell Injury Journal Pathophysiology of Cell Injury Journal 2378-5225 12 1 2023 1 29 Mehmet Arslan MD PhD¹ Ayşe Demir MD The intestinal mucosa exists within a unique physiological oxygen gradient that is essential for maintaining epithelial homeostasis, barrier integrity, immune surveillance, and host–microbiota interactions. Although physiological hypoxia is a normal feature of the intestinal microenvironment, sustained or severe oxygen deprivation initiates a complex cascade of molecular and cellular events that culminate in intestinal epithelial injury and contribute to the pathogenesis of numerous gastrointestinal and systemic disorders. Growing evidence has identified hypoxia as a central driver of intestinal ischemia–reperfusion injury, inflammatory bowel disease, necrotizing enterocolitis, radiation enteropathy, sepsis-associated intestinal dysfunction, and colorectal tumorigenesis. Recent advances in molecular biology have substantially expanded current understanding of the signaling pathways governing hypoxic adaptation and their implications for disease progression and therapeutic intervention. This review provides a comprehensive synthesis of the current evidence regarding the molecular mechanisms underlying hypoxia-induced intestinal cellular injury, emphasizing oxygen-sensing pathways, metabolic reprogramming, mitochondrial dysfunction, oxidative stress, inflammatory signaling, epithelial barrier disruption, and regulated cell death. Particular attention is given to the central role of hypoxia-inducible factors (HIFs), prolyl hydroxylase domain enzymes, AMP-activated protein kinase, mammalian target of rapamycin, and nuclear factor erythroid 2-related factor 2 in coordinating adaptive and maladaptive cellular responses to oxygen deprivation. Furthermore, the review discusses the reciprocal interactions among epithelial cells, immune cells, endothelial cells, and the intestinal microbiota that collectively determine mucosal homeostasis or disease progression under hypoxic conditions. Emerging evidence indicates that prolonged hypoxia promotes mitochondrial dysfunction, excessive reactive oxygen species generation, endoplasmic reticulum stress, inflammasome activation, and disruption of epithelial tight junctions, leading to increased intestinal permeability and amplification of local and systemic inflammatory responses. Concurrent activation of apoptosis, necroptosis, pyroptosis, ferroptosis, and dysregulated autophagy further accelerates epithelial injury and compromises mucosal repair. Advances in single-cell transcriptomics, spatial omics, metabolomics, and artificial intelligence-assisted data analysis are simultaneously improving understanding of intestinal hypoxia while facilitating the discovery of novel biomarkers and therapeutic targets. Pharmacological modulation of HIF signaling, mitochondrial protection, antioxidant defense, epithelial regeneration, microbiome-based therapies, and precision medicine approaches represent promising strategies for mitigating hypoxia-associated intestinal injury. In conclusion, hypoxia-induced intestinal cellular injury is a multifactorial process involving tightly integrated metabolic, mitochondrial, inflammatory, and immune regulatory networks. Continued integration of mechanistic research with translational and clinical investigations will be essential for improving early diagnosis, refining patient stratification, and developing targeted therapeutic interventions. Future advances in multi-omics technologies, systems biology, and precision medicine are expected to transform the prevention and management of hypoxia-associated intestinal diseases and improve clinical outcomes. Keywords: Intestinal hypoxia; Intestinal epithelial injury; Hypoxia-inducible factor; Mitochondrial dysfunction; Oxidative stress. 2023 1 29 10.18081/2378-5225/12.1 https://pcij.net/archives/2663