Endoplasmic Reticulum Stress-Driven Inflammatory Mediators in Metabolic Disorders: From Molecular Mechanisms to Targeted Therapies.
Nutrient overload induces a state of chronic, low-grade inflammation termed metaflammation, which contributes to the development of metabolic disorders, such as type 2 diabetes (T2D) and metabolic dysfunction-associated steatotic liver disease (MASLD). As a nutrient-sensitive organelle, the endoplasmic reticulum (ER) is highly vulnerable to systemic metabolic burden. When its adaptive capacity is exceeded, ER stress (ERS) activates the unfolded protein response (UPR) and drives cellular dysfunction. This review delineates how the canonical UPR sensors transduce metabolic stress into pro-inflammatory signaling cascades. By engaging key transcriptional regulators and inflammasome complexes, these pathways drive the production of inflammatory mediators, including cytokines, chemokines, and bioactive lipids, such as leukotrienes (LTs) and prostaglandins. Subsequently, the review discusses the organ-specific consequences of ERS in the liver, pancreas, adipose tissue, vascular endothelium, and hypothalamus, highlighting how this stress sustains a self-reinforcing cycle of tissue injury and metabolic dysfunction. Emerging therapeutic strategies are also summarized, ranging from broad-spectrum chemical chaperones to precision UPR modulators and organ-targeted delivery systems aimed at disrupting this pathogenic axis and restoring metabolic homeostasis.