Comprehensive analysis of yak milk residue peptides for anti-hypoxic functional foods: targeting neuroinflammation and apoptosis in hypoxic mice

The hypoxia-induced stress response constitutes a physiological disorder that poses a significant, life-threatening risk. This study aims to investigate the anti-hypoxic brain injury effects of peptides derived from yak milk residue and elucidate their underlying mechanisms. Peptidomic analysis identified three bioactive peptides (YPFPGPIPN, PVVPPFLQPEVMGVSK, and T3-LVYPFPGPIPN (T3)) associated with anti-hypoxic activity. <i>In vitro</i> blood-brain barrier (BBB) modeling demonstrated that T3 exhibited significant time- and concentration-dependent permeability. Under hypoxic stress, T3 effectively inhibited neuronal inflammation and apoptosis. Integrated metabolomics and transcriptomics analyses revealed that T3 mitigates hypoxia-induced neuroinflammation by regulating L-glutamine metabolism through the RAS/TNF-α/MAPK signaling pathway. These findings underscore the potential of yak milk residue-derived peptide (T3) as a neuroprotective agent against hypoxic injury. The insights gained from this research are instrumental in utilizing yak milk byproducts and developing functional foods with anti-hypoxia properties, thereby addressing the market needs of specific demographic groups.