Interplay Between Endoplasmic Reticulum Stress and Mitochondrial Dysfunction in Inflammatory Bowel Disease: From...

Endoplasmic reticulum (ER) stress and mitochondrial dysfunction are key pathogenic drivers in inflammatory bowel disease (IBD). Chronic ER stress impairs epithelial barrier integrity and stimulates inflammatory pathways, causing cell death. Simultaneously, mitochondrial dysfunction results in excessive reactive oxygen species production, bioenergetic failure, and defective mitophagy, further disrupting intestinal homeostasis. Notably, these two organellar stress responses are physically and functionally linked via mitochondria-ER contacts (MERCs), which form signaling platforms-mitochondria-associated ER membranes. These platforms coordinate calcium transfer and redox signaling while integrating autophagy and the unfolded protein response (UPR). This review comprehensively summarizes the current molecular mechanisms by which ER stress and mitochondrial dysfunction aid IBD pathogenesis, emphasizing calcium homeostasis imbalance, oxidative stress, disrupted mitochondrial quality control, and autophagy-UPR integration. Furthermore, this article highlights the functional interplay between the ER and mitochondria, as well as the MERCs that structurally connect them. Additionally, it discusses emerging diagnostic biomarkers and therapeutic strategies based on these mechanisms, aiming to offer theoretical insights and novel perspectives for IBD research and clinical intervention.