Crocetin as a Neuroprotective Agent: Targeting Western Diet-Induced Cognitive Dysfunction Through Antioxidant, Anti-Inflammatory and Gut-Brain Axis Modulation.

Western diet-induced cognitive dysfunction is a rapidly emerging health challenge driven by excessive intake of high-fat, high-sugar, and ultra-processed foods. These dietary patterns promote neuroinflammation, oxidative stress, insulin resistance, gut dysbiosis, and blood-brain barrier (BBB) disruption, ultimately leading to synaptic dysfunction and cognitive decline. Crocetin, an apocarotenoid derived from saffron and Gardenia jasminoides, exhibits promising neuroprotective effects by scavenging reactive oxygen species, attenuating neuroinflammatory signaling, enhancing mitochondrial bioenergetics, and improving insulin sensitivity. It further upregulates brain-derived neurotrophic factor (BDNF), modulates PI3K/Akt signaling, and restores gut microbiota balance, thereby reinforcing the gut-brain axis and maintaining BBB integrity. This review further aims to critically assess these mechanistic links by distinguishing well-supported findings from speculative associations emphasizing discrepancies between preclinical and human evidence. Preclinical studies strongly support crocetin's role in ameliorating Western diet-induced neurodegeneration, while early clinical evidence highlights improvements in memory, executive function, and cerebral blood flow. However, limitations such as poor bioavailability, rapid metabolism, and limited large-scale human trials constrain its translation into clinical practice. Advanced formulations, including nanoparticles, liposomes, and prodrug derivatives, hold potential to overcome these challenges. This review critically evaluates the pathophysiological mechanisms of Western diet-induced cognitive decline, highlights the pharmacological actions of crocetin, and discusses its therapeutic prospects within the framework of personalized and precision medicine. Future directions include large-scale randomized controlled trials, pharmacokinetic optimization, and AI-driven predictive models to establish crocetin as a clinically viable neuroprotective agent.