FOXA1 protects against PM2.5-induced chronic lung injury via MARCHF8-dependent mitophagy inhibition.

The function and mechanism of the E3 ubiquitin ligase membrane-associated ring-CH-type finger 8 (MARCHF8) in fine particulate matter (PM2.5)-induced lung injury remain unknown. The effect of MARCHF8 overexpression on PM2.5-induced lung injury in mice was evaluated through lung pathology, apoptosis, and inflammation. The function of MARCHF8 was studied using HBE135-E6E7 and BEAS-2B cells stimulated by PM2.5. Mitochondrial autophagy was evaluated by the protein levels, mt-Keima ratio, MMP, mtROS, and LC3/PINK1/Parkin. The relationship of the FOXA1/MARCHF8/HK2 axis was detected by ChIP, Co-IP and cycloheximide. MARCHF8 expression decreased in PM2.5-exposed mouse lungs, HBE135-E6E7 and BEAS-2B cells, and COPD patients. Overexpressing MARCHF8 reduced PM2.5-induced cellular damage by inhibiting PINK1/Parkin-mediated mitophagy. Mechanistically, FOXA1 overexpression boosted MARCHF8 transcription. MARCHF8 promoted HK2 degradation by catalyzing k48-linked ubiquitination at the K763 site, leading to mitophagy inhibition by obstructing PINK1/Parkin recruitment. Furthermore, FOXA1 alleviated PM2.5-induced lung injury by inhibiting mitophagy via the MARCHF8/HK2/Parkin axis, and HK2 overexpression counteracted the protection against PM2.5-induced cytotoxicity provided by MARCHF8 or FOXA1. Meanwhile, the correlation between FOXA1, MARCHF8, and HK2 was validated in clinical samples of COPD patients. In conclusion, FOXA1 overexpression mitigates PM2.5-induced lung injury by suppressing mitophagy via the MARCHF8/HK2/Parkin axis, which may be a promising therapeutic strategy in the future.