5-Methoxytryptophan attenuates hypobaric hypoxia induced acute lung injury by alleviating lipid peroxidation via targeting peroxiredoxin 6.

Summary

In a human high-altitude exposure cohort and complementary mouse/cell models, plasma and tissue 5-MTP fell with hypoxia and correlated with desaturation and acute mountain sickness. Exogenous 5-MTP bound Prdx6 at Ser32, preventing its lysosomal degradation, limiting lipid peroxidation, and preserving endothelial barrier integrity, thereby attenuating hypoxia-induced acute lung injury.

Key Findings

• In 40 humans ascending from 200 m to 4260 m, plasma 5-MTP decreased and correlated with oxygen desaturation and acute mountain sickness.
• Hypoxia downregulated Asmt via NF-κB p50 promoter binding; si-Hif1α or NF-κB inhibition restored Asmt and 5-MTP.
• 5-MTP directly bound Prdx6 at Ser32 (proteolysis-MS, docking, CETSA, MST), preventing lysosomal degradation and lipoperoxidation.
• 5-MTP reduced endothelial hyperpermeability and barrier disruption; Prdx6-S32A abrogated protective effects in vitro and in vivo.

Clinical Implications

5-MTP measurement could stratify risk for hypoxic maladaptation (e.g., high-altitude exposure). Pharmacologic augmentation of 5-MTP or Prdx6-stabilizing strategies may emerge as adjuncts to prevent/treat acute lung injury pending clinical trials.

Limitations

• Human component is correlational with a modest sample size (n=40)
• No randomized clinical intervention to test therapeutic efficacy

Future Directions

Prospective trials testing 5-MTP supplementation in high-altitude exposure or ALI, medicinal chemistry to enhance Prdx6 stabilization, and pharmacokinetics/safety profiling in humans.