Phycocyanobilin as a Functional Food-Derived Nutraceutical Candidate for Modulating the RAGE/NOX4 Axis in Neurodegenerative Disorders

<b>Background/Objectives:</b> Neurodegeneration associated with diabetes and metabolic dysfunction involves interconnected processes, including advanced glycation end product (AGE)-related signaling, RAGE/NOX4-dependent oxidative stress, dysregulated endoplasmic reticulum (ER) stress, and mitochondrial apoptosis. Phycocyanobilin (PCB), a tetrapyrrolic chromophore of <i>C</i>-phycocyanin, has been proposed to exert pleiotropic cytoprotective effects; however, its actions within glycation-associated neuronal stress pathways remain incompletely defined. <b>Methods:</b> Differentiated SH-SY5Y neurons were exposed to AGEs (300 μg/mL) for a 24 h period to examine whether PCB modulates neuronal injury along the RAGE-NOX4-oxidative-stress-ER-stress-mitochondrial axis. The selective RAGE antagonist TTP488 (100 μmol/L) was included as a pharmacological reference. Neuronal viability, neurite integrity, intracellular and mitochondrial reactive oxygen species, ER stress signaling, and apoptotic markers were assessed using complementary biochemical, molecular, and functional assays. <b>Results:</b> PCB pretreatment (10-50 μmol/L) significantly improved neuronal viability, preserved neurite structure, and reduced oxidative stress under the AGE challenge. These effects were accompanied by attenuation of AGEs-induced upregulation of RAGE and NOX4 expression, suppression of PERK-eIF2α-ATF4-CHOP signaling, restoration of mitochondrial apoptotic balance, inhibition of caspase activation, and reduced DNA fragmentation. The overall protective profile of PCB was comparable to that observed with TTP488 at the level of downstream pathway modulation. <b>Conclusions:</b> These findings suggest that PCB mitigates glycation-associated neuronal injury through coordinated regulation of oxidative, ER stress, and mitochondrial apoptotic pathways linked to RAGE/NOX4 signaling, supporting further investigation of PCB as a functional food-derived bioactive in metabolic stress-related neurodegeneration.