Molecular interplay between oxidative and endoplasmic reticulum stress in multiple sclerosis

Multiple sclerosis (MS) is a debilitating neurological condition driven by immune-mediated damage to the central nervous system (CNS), leading to myelin destruction and progressive nerve fiber impairment. Recent studies have identified oxidative stress and endoplasmic reticulum (ER) stress as pivotal contributors to MS pathology. When antioxidant defenses fail to neutralize excessive reactive oxygen species (ROS), oxidative damage occurs, harming lipids, proteins, and DNA within neural cells. This oxidative injury worsens mitochondrial dysfunction and sustains chronic inflammation, accelerating disease advancement. Meanwhile, ER stress emerges when misfolded proteins overload the organelle's folding capacity, prompting the unfolded protein response (UPR) to mitigate the crisis. However, prolonged ER stress can shift cellular signaling toward apoptosis, particularly damaging oligodendrocytes and axons in MS. A critical bidirectional relationship exists between these stress pathways-oxidative disturbances disrupt ER protein folding and calcium balance, while unresolved ER stress generates further oxidative radicals. Together, they amplify neuroinflammation, impair glial function, and drive neurodegeneration, making them attractive targets for intervention. Current research explores compounds such as ROS scavengers, ER stress alleviators, and UPR regulators to counteract these mechanisms. Unraveling the interplay between oxidative and ER stress could unlock new treatment avenues to modify MS progression. This review synthesizes current knowledge on their synergistic effects, discusses emerging therapeutic strategies, and highlights gaps for future investigation.