Antioxidants & redox signaling · 2026
BACH2 Exacerbates Bronchopulmonary Dysplasia by Promoting NCOA4-Dependent Ferritinophagy via Transcriptional Activation of JUN.
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Zhao Menghua, Wu Yizhong, Wu Bufei, Xu Jun, Wang Duane, Huang Furong, Zhang Aimin, Huang Li, Wu Xu
Аннотация
AIMS: This study investigated whether BACH2 affects bronchopulmonary dysplasia (BPD) through ferritinophagy and elucidated its molecular mechanisms.
RESULTS: JUN was identified as a key gene linking BPD and ferritinophagy, showing elevated expression in preterm neonates with BPD and in hyperoxia-exposed alveolar epithelial cells (MLE12). In the cellular BPD model, knockdown of either JUN or its upstream regulator, BACH2, inhibited hyperoxia-induced nuclear receptor coactivator 4 (NCOA4)-dependent ferritinophagy, accompanied by restored cell viability and mitigated oxidative stress, autophagy flux, and ferroptosis. Functional rescue experiments confirmed NCOA4 as the critical downstream effector of JUN, and JUN overexpression reversed the protective effects of BACH2 silencing. Mechanistically, BACH2 activates JUN transcription, thereby augmenting c-Jun phosphorylation and the activity of the downstream AP-1 complex. In a neonatal mouse BPD model, BACH2 knockdown attenuated hyperoxia-induced lung injury, improved alveolarization and vascular remodeling, and suppressed the BACH2/c-Jun/NCOA4 pathway, ferritinophagy, and ferroptosis in lung tissues.
INNOVATION: This study delineates a novel pathogenic axis in which BACH2 drives ferritinophagy-mediated ferroptosis in BPD by transcriptionally upregulating JUN, which, in turn, promotes NCOA4-dependent ferritinophagy, highlighting BACH2 and c-Jun as potential therapeutic targets.
CONCLUSION: BACH2 exacerbates BPD by transcriptionally activating JUN, which promotes NCOA4-dependent ferritinophagy and ferroptosis. Targeting this axis offers a potential therapeutic strategy for BPD. Antioxid. Redox Signal. 45, 693-713.
RESULTS: JUN was identified as a key gene linking BPD and ferritinophagy, showing elevated expression in preterm neonates with BPD and in hyperoxia-exposed alveolar epithelial cells (MLE12). In the cellular BPD model, knockdown of either JUN or its upstream regulator, BACH2, inhibited hyperoxia-induced nuclear receptor coactivator 4 (NCOA4)-dependent ferritinophagy, accompanied by restored cell viability and mitigated oxidative stress, autophagy flux, and ferroptosis. Functional rescue experiments confirmed NCOA4 as the critical downstream effector of JUN, and JUN overexpression reversed the protective effects of BACH2 silencing. Mechanistically, BACH2 activates JUN transcription, thereby augmenting c-Jun phosphorylation and the activity of the downstream AP-1 complex. In a neonatal mouse BPD model, BACH2 knockdown attenuated hyperoxia-induced lung injury, improved alveolarization and vascular remodeling, and suppressed the BACH2/c-Jun/NCOA4 pathway, ferritinophagy, and ferroptosis in lung tissues.
INNOVATION: This study delineates a novel pathogenic axis in which BACH2 drives ferritinophagy-mediated ferroptosis in BPD by transcriptionally upregulating JUN, which, in turn, promotes NCOA4-dependent ferritinophagy, highlighting BACH2 and c-Jun as potential therapeutic targets.
CONCLUSION: BACH2 exacerbates BPD by transcriptionally activating JUN, which promotes NCOA4-dependent ferritinophagy and ferroptosis. Targeting this axis offers a potential therapeutic strategy for BPD. Antioxid. Redox Signal. 45, 693-713.