Ferroptosis: A potential mechanistic link to neuronal death and demyelination in MS-related depression.

Multiple sclerosis (MS) is a chronic neuroinflammatory disorder, and approximately 50% of MS patients develop depression, making it one of the most common comorbidities of the disease. MS-related depression significantly reduces quality of life, worsens neurological disability, and increases suicide risk. Despite its high prevalence, the underlying mechanisms remain unclear. While neuroinflammation and neurotransmitter dysregulation have been implicated, recent evidence suggests that ferroptosis, an iron-dependent form of cell death, may contribute to both neuronal death and mood disturbances in MS patients. Ferroptosis is driven by iron accumulation, lipid peroxidation (LPO), and oxidative stress, all of which are elevated in MS lesions. The inflammatory environment in MS may exacerbate ferroptosis-related processes, potentially contributing to demyelination, neuronal dysfunction, and altered neurotransmitter metabolism-factors strongly linked to depressive symptoms. This review examines the potential role of ferroptosis in MS progression and MS-related depressive symptoms, with a particular focus on oxidative damage and inflammatory signaling related to iron metabolism in the central nervous system (CNS). Understanding these mechanisms may inform future therapeutic hypotheses for MS patients suffering from depression.