Citrus phytochemicals in neurodegenerative diseases: Preclinical evidence and clinical potential

Citrus fruits are abundant sources of bioactive phytochemicals, including flavonoids, terpenoids, and coumarins, that exhibit potent antioxidant, anti-inflammatory, and neuroprotective effects. With the rising global burden of Alzheimer’s disease (AD), Parkinson’s disease (PD), and other neurodegenerative disorders, these compounds have attracted growing attention for their potential to counter oxidative stress, neuroinflammation, protein aggregation, and synaptic dysfunction. Unlike previous reviews focusing on individual compounds or isolated disease models, this work provides an integrative synthesis that links citrus phytochemicals to cross-disease mechanisms, translational applications, and sustainability perspectives. A structured literature search of PubMed, Scopus, Web of Science and Google Scholar identified peer-reviewed studies addressing citrus-derived bioactives in neurodegenerative models. Data were categorized by compound class, disease context, and mechanistic axis, emphasizing redox modulation, autophagy/apoptosis, amyloid regulation, and neurotransmission. Citrus phytochemicals demonstrated multimodal neuroprotection. Naringin and hesperidin reduced amyloid pathology and improved cognition in AD models, while nobiletin and limonene preserved dopaminergic neurons in PD. These compounds enhanced neurotransmission and promoted neurotrophic factor-mediated plasticity. Integrating phyto-nanomedicine approaches addressed bioavailability barriers, and citrus-waste valorization provided sustainable compound sources. This review uniquely unifies mechanistic, translational, and ecological dimensions of citrus neuroprotection. By identifying key knowledge gaps and future research priorities, it establishes a novel conceptual framework for developing citrus-derived nutraceuticals and nano delivery systems as accessible, sustainable, and clinically relevant interventions for brain health. • Citrus phytochemicals act on oxidative stress, neuroinflammation, aggregation, and synaptic dysfunction. • Naringin, hesperidin, nobiletin, and limonene show multimodal neuroprotection in AD and PD models. • Citrus bioactives regulate NF-κB, Nrf2, apoptosis, autophagy, and neurotransmission pathways. • Phyto-nanomedicine enhances bioavailability and supports translational neurotherapeutic potential.