Targeting the Gut-Brain-Ferroptosis Axis: Molecular Mechanisms and Therapeutic Potential in Alzheimer's Disease and Epilepsy.

Alzheimer’s disease (AD) and epilepsy share underlying mechanisms of oxidative stress and neuroinflammation, yet effective targeted therapies remain limited. This review presents a novel integrative model linking gut microbiota dysbiosis to ferroptosis, an iron-dependent form of regulated cell death. We propose a vicious cycle in which dysbiosis promotes systemic inflammation and disrupts cerebral iron homeostasis, impairing the glutathione/GPX4 antioxidant system and sensitizing neurons to lipid peroxidation and ferroptotic death. This neuronal damage further fuels neuroinflammation and may exacerbate gut barrier dysfunction. Evidence from both conditions reveals altered gut microbiota alongside ferroptosis markers such as iron accumulation, reduced GPX4, and elevated lipid peroxides. Therapeutically, we examine two complementary approaches: central inhibition of ferroptosis using specific inhibitors and iron chelators, and peripheral modulation of the gut-brain axis via probiotics, prebiotics, or fecal transplantation. Preclinical studies indicate that targeting either pathway can reduce pathology and improve outcomes. We conclude that the most promising strategy involves combined therapies that simultaneously inhibit ferroptosis and restore gut microbial balance, offering a novel, multi-target approach to disrupt the pathogenic cycle in AD and epilepsy.