PARK7 alleviates high-altitude pulmonary edema by suppressing BACH1 to attenuate lipid peroxidation-driven pro-inflammatory skewing of macrophages.

BACKGROUND

With the steady increase in global travel, mountaineering, and logistics at extreme elevations, high-altitude pulmonary edema (HAPE) remains a life-threatening emergency with mortality rates reaching up to 50% if untreated. Current clinical management relies heavily on rapid descent or supplemental oxygen, which are often logistically unfeasible in remote areas, while existing pharmacological interventions face challenges regarding efficacy and side effects. There is an urgent need to identify the fundamental molecular switches that translate hypobaric hypoxia into the catastrophic "cytokine storm" and barrier failure characteristic of HAPE. This study investigates the role of the antioxidant protein parkinsonism associated deglycase (PARK7) as a potential therapeutic target.

METHODS

A mouse model simulating 6000 m altitude (72 h) and CoCl₂-induced hypoxia in MLE-12 and RAW264.7 cells were used. PARK7 expression in lung tissue and hypoxic cells was analyzed via RNA-seq, qPCR, and western blot analyses. Lung-specific PARK7 and Bach1 overexpression or knockdown was achieved using AAV9-mediated intratracheal instillation. Pulmonary edema, vascular permeability, histopathology, and ultrastructure were assessed. Lipid peroxidation and M1 macrophage polarization (F4/80⁺iNOS⁺) were evaluated using C11-BODIPY staining, 4-HNE immunohistochemistry, and flow cytometry.

RESULTS

PARK7 expression was markedly reduced in HAPE lungs and hypoxic cells. Restoration of PARK7 alleviated pulmonary edema, barrier dysfunction, mitochondrial damage, and inflammatory cell infiltration, primarily macrophages. Mechanistically, PARK7 suppressed lipid peroxidation, reducing MDA and 4-HNE accumulation, thereby blocking pro-inflammatory M1 macrophage polarization. Hypoxia stabilized the antioxidant repressor BTB and CNC Homology 1 (BACH1), whereas PARK7 inhibited BACH1 to exert its protective effect. Re-expression of BACH1 negated PARK7's benefits, restoring lipid peroxidation and M1 macrophage infiltration.

CONCLUSION

This study suggests PARK7 as a key protective factor during HAPE progression. PARK7 inhibits lipid peroxidation through downregulation of BACH1, thereby preventing pro-inflammatory M1 polarization of macrophages and ultimately preserving alveolar-capillary barrier integrity. Targeting the PARK7-BACH1 axis may offer a novel therapeutic strategy for the prevention and treatment of HAPE.