β-sitosterol and next-generation neuroprotection for multi-target strategies and the gut-brain axis in neurodegenerative diseases

Neurodegenerative disorders such as Alzheimer's and Parkinson's diseases arise from complex interactions among oxidative stress, neuroinflammation, metabolic dysfunction, and dysregulated signaling networks. This review aim of the synthesize mechanistic evidence on β-sitosterol as a multi-target phytochemical and clarify how its actions connect to gut-brain axis modulation in neurodegeneration. The integrated mechanistic framework linking β-sitosterol's effects on cholesterol homeostasis, neuroinflammation, mitochondrial function, cholinergic signaling, and microbiota-barrier integrity to cognitive outcomes. Scope: preclinical and early translational evidence on β-sitosterol alone and with complementary phytochemicals, including nano-delivery strategies. Increasing evidence highlights phytochemicals as promising multi-target therapeutic agents capable of modulating these interconnected pathological processes. β-Sitosterol exhibits broad activity by regulating cholesterol metabolism, suppressing neuroinflammation, restoring redox balance, preserving mitochondrial function, and inhibiting important Alzheimer's diseases targets, including acetylcholinesterase and butyrylcholinesterase. The mechanisms action of β-sitosterol may (i) dampen microglial activation via TLR4/NF-κB signaling, (ii) activate Nrf2-dependent antioxidant responses (Nrf2/HO-1), (iii) support mitochondrial function and reduce ROS, (iv) stabilize membrane cholesterol and modulate amyloidogenic processing, and (v) inhibit acetylcholinesterase/butyrylcholinesterase to restore cholinergic tone. Complementary showing a neuroprotective effect actions of other phytochemicals such as curcumin, resveratrol, sulforaphane, and sinapic acid further enhance neuroprotection by modulating pathways like Nrf2/HO-1, TLR4/NF-κB, PI3K/Akt, and autophagy. Collectively, preclinical studies demonstrate that diverse botanical extracts significantly improve cognitive performance, reduce amyloid burden, restore cholinergic function, and attenuate neuroinflammation and oxidative damage. Emerging preclinical evidence suggests in rodent models of amyloid pathology, β-sitosterol (5-50 mg/kg) has been reported to improve memory in behavioral tests and reduce markers of neuroinflammation and oxidative stress; gut-brain effects include microbiota remodeling and enhanced barrier integrity, which correlate with reduced neuroimmune activation. Advances in nano-delivery systems and functional food formulations substantially improve phytochemical stability, bioavailability, and brain targeting. Available evidence is chiefly preclinical; clinical translation will require standardized dosing, pharmacokinetic and blood-brain barrier penetration studies, and randomized trials with microbiome and cognitive endpoints. Collectively, these findings position phytochemicals as promising candidates for multi-target disease modification and the development of next-generation neurotherapeutic strategies.