The Keap1/Nrf2/ARE/HO-1 axis in epilepsy: Crosstalk between oxidative stress and neuroinflammation

Epilepsy is a complex neurological disorder characterized by recurrent seizures, which are driven by multifaceted pathophysiological mechanisms, including oxidative stress and neuroinflammation. Despite advancements in anti-seizure medications (ASMs), a significant proportion of patients remain resistant to treatment, highlighting the need for novel therapeutic strategies. This review focuses on the Kelch-like ECH-associated protein 1 (Keap1) / Nuclear factor erythroid 2-related factor 2 (Nrf2) / Antioxidant Response Element (ARE) / Heme Oxygenase-1 (HO-1) axis as a promising target for neuroprotection in epilepsy. We explored the intricate interactions between Keap1 and Nrf2 under homeostatic conditions and how oxidative stress disrupts this balance, triggering Nrf2 activation. This review details the subsequent process of Nrf2 nuclear translocation, its binding to AREs, and the induction of cytoprotective gene expression, which collectively orchestrate a robust cellular defense response. Special emphasis is placed on HO-1, a key effector of Nrf2-mediated neuroprotection, highlighting its enzymatic function and protective mechanisms, including antioxidant, anti-inflammatory, and anti-apoptotic effects. Additionally, the review examines HO-1's role in mitigating seizure-induced neuronal damage. However, challenges remain, including variability in therapeutic responses, gaps in long-term clinical validation, and the need for standardized protocols. Future research should focus on biomarkers for personalized treatment, advanced imaging, and genetic tools to explore the Keap1/Nrf2/ARE/HO-1 axis in greater depth. Future studies should focus on overcoming the challenges of translating preclinical findings into clinical applications and exploring the long-term effects of targeting this pathway in epilepsy treatment.