Nootkatone confers MAOB-dependent neuroprotection against ferroptotic injury via brain-targeted nanoparticle delivery in ischemic stroke.

Abstract

BACKGROUND: Despite advances in reperfusion therapy, effective neuroprotective interventions for ischemic stroke that can be reliably translated into clinical benefit are lacking. A persistent obstacle is the frequent disconnect between mechanistic validity and effective drug exposure within the injured brain, a limitation that is particularly evident for natural products with pleiotropic but weakly defined modes of action. Nootkatone (NKT), a naturally occurring sesquiterpenoid, has antioxidant and neuroprotective activity, yet its direct molecular target and translational limitations in ischemic stroke remain unresolved. This study aimed to define a target-anchored mechanism for NKT and to determine whether improving brain exposure is required to translate this mechanism into effective neuroprotection. RESULTS: Through an integrative disease-informed target discovery strategy combining network-based prediction, structure-informed docking, and cross-species biochemical validation, monoamine oxidase B was identified as the primary molecular target engaged by NKT. Pharmacological inhibition or genetic suppression of monoamine oxidase B (MAOB) activated an Nrf2-dependent antioxidant program, reinforced glutathione homeostasis, suppressed lipid peroxidation and ferroptotic injury, preserved mitochondrial integrity, and conferred robust neuroprotection in neuronal oxygen-glucose deprivation models and in mice subjected to transient cerebral ischemia. NKT was encapsulated within a hyaluronic acid modified polyethylene glycol nanocarrier engineered to increase circulation stability and lesion-associated accumulation and to improve brain exposure. This nanodelivery strategy markedly strengthened the neuroprotective efficacy and functional recovery in vivo while preserving the same intracellular signaling mechanisms observed with the free compound, indicating improved pharmacological activity rather than altered bioactivity. CONCLUSIONS: These findings establish MAOB as a druggable mitochondrial redox regulator underlying NKT-mediated neuroprotection. In parallel, the results demonstrated that insufficient brain exposure represents a critical barrier to converting this mechanism into a consistent therapeutic benefit after stroke. By resolving both target definitions and exposure limitations within a single experimental framework, this study explains a major source of inconsistency in natural product-based neuroprotection and provides a practical strategy for achieving reproducible neuroprotective efficacy in ischemic stroke.

Key Findings

• Nootkatone (NKT) targets monoamine oxidase B (MAOB) to activate an Nrf2-dependent antioxidant program.
• Inhibition or suppression of MAOB by NKT suppresses lipid peroxidation and ferroptotic injury, preserves mitochondrial integrity, and provides neuroprotection in ischemic stroke models.
• Encapsulation of NKT in a hyaluronic acid modified polyethylene glycol nanocarrier improves brain exposure, enhances neuroprotective efficacy, and promotes functional recovery in vivo.

Clinical Significance

Citation

Zhang Yonggang, Feng Shi, Yu Kaiet al.. Nootkatone confers MAOB-dependent neuroprotection against ferroptotic injury via brain-targeted nanoparticle delivery in ischemic stroke. Journal of nanobiotechnology. 2026-May-10.