Arabica coffee oil extract enhances neuronal resilience under hypoxic stress through HIF-1α and EGFR signaling modulation

Background: Hypoxia is a critical factor contributing to neuronal injury, primarily through dysregulation of hypoxia-inducible factor-1 alpha (HIF-1α). This study aimed to investigate the neuroprotective effects of Arabica coffee oil extract under hypoxic conditions in neuronal cells and to elucidate the underlying molecular mechanisms. Methods: Human SH-SY5Y neuron-like cells were exposed to cobalt chloride (CoCl₂) to induce chemical hypoxia. Hypoxic conditions were validated by quantitative PCR analysis of gene expression and by observation of neuronal morphology. Proteomic profiling using LC-MS/MS was then performed to identify differentially expressed proteins (DEPs) and enriched biological pathways, in order to elucidate the molecular mechanisms underlying Arabica oil extract–mediated modulation. Results: Hypoxic stress significantly altered the expression of genes and proteins associated with vesicular trafficking, protein folding, and transcriptional regulation, along with morphological changes indicative of synaptic loss. One-hour pretreatment with Arabica oil extract markedly mitigated these effects, restoring 841 DEPs to expression patterns resembling normoxic conditions. Enrichment analyses revealed that Arabica pretreatment supported mitochondrial function, calcium signaling, and synaptic organization, while maintaining proteostasis through regulation of HIF-1–dependent and EGFR-associated pathways. Conclusion: Arabica coffee oil extract confers neuroprotection under hypoxic stress by restoring protein homeostasis, preserving synaptic integrity, and modulating key stress-response and translational pathways. These findings provide novel insight into the molecular mechanisms by which Arabica oil extract enhances neuronal resilience to hypoxic injury.