Abstract

Background: Neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease and related syndromes represent a growing global health burden with current therapies largely limited to symptomatic relief rather than disease modification. By 2025, increasing evidence indicates that mono-target pharmacological approaches fail to address the interconnected cellular dysfunctions underlying neurodegeneration, including oxidative stress, mitochondrial failure, chronic neuroinflammation, impaired autophagy and synaptic disintegration. 
Objective: This review aims to critically evaluate β-sitosterol as a multi-target neuroprotective phytosterol and elucidate its role in modulating key cellular signalling pathways involved in neurodegenerative progression. 
Methods: Recent experimental and translational studies were systematically analysed to assess the molecular mechanisms through which β-sitosterol regulates neuronal and glial signalling networks with emphasis on antioxidant defence, inflammatory modulation, mitochondrial stabilization and proteostasis control. 
Results: β-Sitosterol demonstrates pleiotropic neuroprotective actions through activation of Nrf2-ARE signalling, suppression of NF-κB-mediated neuroinflammation, modulation of PI3K/Akt/GSK-3β survival pathways and restoration of AMPK-mTOR-regulated autophagy. Its structural similarity to cholesterol further enables regulation of membrane lipid rafts, synaptic integrity and calcium homeostasis, collectively enhancing neuronal resilience across multiple neurodegenerative models. 
Conclusion: β-Sitosterol emerges as a promising disease-modifying neuroprotective agent capable of restoring cellular signalling balance rather than targeting isolated pathological endpoints, supporting its potential role in next-generation neurotherapeutic strategies.