Targeting the Fra2/LCN2 axis attenuates PM2.5-aggravated asthma by suppressing M2 macrophage ferroptosis.

Exposure to fine particulate matter (PM2.5) is a well-established environmental trigger of asthma exacerbations; however, the mechanistic link to macrophage ferroptosis remains elusive. This study identifies a novel pathway by which PM2.5 promotes asthma pathogenesis by activating the Fos-related antigen 2 (Fra2)/Lipocalin 2 (LCN2) axis, thereby inducing ferroptosis in M2 macrophages. We validated this in vivo using a macrophage-specific LCN2-knockdown mouse model delivered via an adeno-associated virus 9 vector. PM2.5-exposed M2 macrophages were analyzed in vitro using integrated multi-omics profiling, chromatin immunoprecipitation followed by quantitative PCR (ChIP-qPCR), transmission electron microscopy, and functional assays assessing mitochondrial integrity and ferroptosis markers. PM2.5 exposure disrupted macrophage polarization equilibrium, while multi-omics analyses revealed significant ferroptosis pathway enrichment and identified LCN2 as a central regulator. Mechanistically, PM2.5 activated the transcription factor Fra2, promoting its direct binding to the LCN2 promoter and upregulating LCN2 expression. The Fra2/LCN2 axis activation triggers ferroptosis via coordinated downregulation of FTH1 and upregulation of ACSL4 and PTGS2. This mitophagy dysfunction aggravated mitochondrial damage and intracellular iron accumulation, as evidenced by increased P62 levels and decreased LC3B levels, ultimately promoting ferroptosis in M2 macrophages. Critically, macrophage-specific knockdown of LCN2 reversed PM2.5-induced mitophagy inhibition and ferroptosis, thereby effectively attenuating airway inflammation and impaired lung function in asthmatic mice. Collectively, these findings reveal a previously unrecognized mechanism whereby PM2.5 exacerbates asthma through Fra2/LCN2-mediated mitophagy dysfunction and ferroptosis in M2 macrophages. Consequently, the Fra2/LCN2 axis may represent a potential therapeutic target for environment-associated asthma.