Joanna Harasym, Alona Tiupova, Ewa Pejcz
In vitro and in vivo evidence demonstrates that EGT exerts neuroprotective effects through multiple mechanisms: scavenging reactive oxygen species, suppressing neuroinflammatory cytokines (TNF-α, IL-1β, IL-6), activating Nrf2 antioxidant pathways, and preserving mitochondrial integrity. Low blood EGT levels correlate with cognitive decline and dementia, supporting its role as a conditionally essential micronutrient for healthy aging. Mushroom by-products retain EGT concentrations comparable to commercial fruiting bodies, making them viable sources for dietary supplements and functional foods. Mushroom processing generates substantial residual biomass-including stems, culls, and spent substrate-that represents an underexploited dietary source of ergothioneine (EGT), a naturally occurring antioxidant with exceptional neuroprotective and anti-inflammatory properties. Since humans cannot synthesize EGT endogenously, dietary intake is essential for maintaining neuroprotection against neurodegenerative diseases. This review examines sustainable extraction strategies-including hot-water, ultrasound-assisted, and high-hydrostatic-pressure methods-enabling integration into circular biorefinery systems. Applications in nutraceuticals and pharmaceuticals targeting oxidative stress-related neurodegeneration are highlighted. Despite challenges in standardization and regulatory approval, valorizing mushroom residuals offers a sustainable pathway to increase dietary availability of this neuroprotective antioxidant, supporting both environmental sustainability and therapeutic innovation for neurodegenerative disease prevention.