Targeting the microbiome-NLRP3-ferroptosis axis in multiple sclerosis: Neuropharmacological implications for microglial dysfunction and demyelination.

Multiple sclerosis (MS) is a chronic autoimmune disorder of the central nervous system (CNS) characterized by neuroinflammation, demyelination, and neurodegeneration. Recent evidence has established a mechanistic connection between gut microbial dysbiosis, the activation of the NOD-like receptor protein 3 (NLRP3) inflammasome, and ferroptosis, an iron-dependent regulated cell death marked by lipid peroxidation. This review synthesizes current understanding of how alterations in the gut microbiome disrupt the gut-brain axis and compromise the blood-brain barrier (BBB), thereby promoting the activation of the microglial NLRP3 inflammasome in the central nervous system. The resulting neuroinflammatory milieu, marked by oxidative stress and iron dysregulation, renders oligodendrocytes and neurons susceptible to ferroptosis via essential enzymes like ACSL4 and ALOX15. We examine the reciprocal relationship between NLRP3-induced inflammation and ferroptotic cell death, emphasizing microglia as crucial mediators of this detrimental cycle. We explore innovative neuropharmacological strategies targeting the gut microbiota, NLRP3 inhibition, and ferroptosis pathways (e.g., ACSL4/ALOX15 inhibitors) to achieve neuroprotection and reduce disease progression. This extensive perspective enhances understanding of MS pathophysiology and identifies actionable therapeutic targets within the microbiome-inflammasome-ferroptosis axis for the development of mechanism-based therapies.