Restoring BECN1-mediated autophagy mitigates acute lung injury caused by zinc oxide nanoparticles

Pulmonary inhalation of zinc oxide nanoparticles (ZnONPs) triggers metal fume fever in humans and acute lung injury (ALI) in animal experiments. Previous evidence suggests that autophagy is involved in the pathogenesis of ZnONPs-induced ALI, with BECN1/Beclin1-dependent autophagy and mitophagy playing a central role. In the present study, heterozygous-deficient (Becn1^+/-) mice exhibit significantly exacerbated ALI compared to Becn1^+/+ controls following ZnONPs exposure. Immunoprecipitation-mass spectrometry analysis revealed that ZnONPs remodel the BECN1 protein interactome, enriching pathways related to autophagy, mitophagy, and mitochondrial quality control. Furthermore, Becn1 haploinsufficiency disrupted autophagic progression, causing accumulation of dysfunctional mitochondria within mitophagosomes. Notably, administration of Tat-Beclin1, a cell-permeable autophagy-inducing peptide, effectively ameliorated ZnONPs-induced ALI in both Becn1^+/+ and Becn1^+/- mice exposed to ZnONPs. Crucially, macrophage-specific Becn1 knockout mice recapitulated the exacerbated injury phenotype, identifying myeloid BECN1 as the critical cellular protector. Mechanistically, Tat-Beclin1 restored autophagic progression and facilitated mitochondrial degradation, thereby attenuating ROS production and inflammatory cascades. These findings demonstrate that pharmacological restoration of BECN1 via Tat-Beclin1 offers a viable strategy for treating nanoparticle-induced metal fume fever and ALI.