Characterization and Evaluation of the Neuroprotective Potential of Peptides Derived from Holothuria scabra Inner Wall Proteins: An In Vitro Study

Neurodegenerative diseases are characterized by progressive neuronal dysfunction driven by interconnected mechanisms, including oxidative stress, apoptosis, and impaired protein homeostasis. Marine-derived proteins and peptides represent promising sources of multifunctional neuroprotective agents; however, the neuroprotective potential of gastrointestinal digestion-derived peptides from Holothuria scabra remains poorly characterized. This study investigated the neuroprotective effects of a gastrointestinal digest of H. scabra inner-wall proteins (IWD), a mixture of digestion-derived peptides, in an OA-induced SH-SY5Y cell model. The original protein extract (IW) was characterized by LC–MS/MS and PANTHER, while IWD-derived peptides were profiled by LC–MS/MS and evaluated using in silico bioactivity and ADMET prediction. In vitro, IWD pretreatment significantly attenuated OA-induced neuronal injury by reducing intracellular ROS accumulation while preserving cell viability and neuronal morphology; 5 μg/mL showed the strongest protective effect. Proteomic analysis identified STMN1 as a major discriminator associated with neuronal structural adaptation, while RPS27A and RPLP2 were associated with translational regulation. HSPB1, HSP90AB1, and PARK7 emerged as additional candidate proteins related to cellular stress responses and homeostasis. Integrated proteomic and network analyses further highlighted proteins associated with ribosomal function, RNA processing, and proteostasis. These findings suggest that IWD-associated neuroprotection involves coordinated changes in neuronal structure and cellular maintenance pathways, supporting further validation of H. scabra-derived peptides as potential neuroprotective candidates.