Abstract Rationale Zinc transporters play a critical role in maintaining intracellular zinc equilibrium, which influences a wide spectrum of physiological and pathological pathways. Nevertheless, their specific involvement in the pathogenesis of acute lung injury (ALI) and its severe clinical form, acute respiratory distress syndrome (ARDS), has not been fully elucidated. Methods The expression of zinc transporters, with a focus on ZIP1, was assessed in lung samples obtained from patients with ARDS and a murine model of ALI. The study employed a combination of models-including AT2 cell-specific Zip1-knockout and overexpressing mice, Lc3b- or Tfe3-deficient mice, primary rat AT2 cells, and human alveolar epithelial lines (A549 and BEAS-2B)-to investigate the role of ZIP1. Furthermore, an integrated approach of computational simulation and high-throughput compound screening was utilized to identify ZIP1 agonists. Results Our analysis revealed a significant upregulation of ZIP1 specifically within alveolar type 2 (AT2) cells from both human ARDS lungs and experimental ALI models. AT2 cell-specific genetic depletion of Zip1, as well as pharmacological zinc chelation, markedly exacerbated the severity of lung injury. Conversely, AT2-specific ZIP1 overexpression or dietary zinc supplementation conferred substantial protective effects. Crucially, the therapeutic benefit of zinc supplementation was abolished in AT2-specific Zip1-deficient mice, unequivocally establishing ZIP1 as the indispensable mediator of zinc-dependent protection in ALI. Mechanistically, our data suggest that zinc influx, facilitated by ZIP1, leads to the activation of transcription factors TFEB, TFE3, and MITF. This activation triggers a protective autophagic response that promotes the clearance of damaged mitochondria while simultaneously suppressing apoptotic and pyroptotic cell death pathways in AT2 cells. The persistence of severe injury in Lc3b- or Tfe3-deficient mice, unalleviated by zinc treatment, further validates this pathway. We further confirmed that ZIP1 functions upstream of autophagy, as lung injury in Zip1-deficient mice was not aggravated by additional knockdown of Lc3b. Furthermore, we identified CQMU-5 as a novel and specific agonist of ZIP1. Treatment with CQMU-5 significantly mitigated lung injury across diverse murine models, including those induced by Streptococcus pneumoniae infection, cecal ligation and puncture, and endotoxin instillation. Conclusion Zinc transporter ZIP1 in alveolar epithelial cells is a central defender against ALI, orchestrating a protective mechanism via zinc-dependent activation of autophagy. These findings not only elucidate a previously unrecognized ZIP1-zinc-autophagy axis critical for lung integrity but also highlight the therapeutic potential of targeting ZIP1. Consequently, pharmacological activation of ZIP1 emerges as a promising and translatable strategy for the treatment of ALI and ARDS. This abstract is funded by: National Natural Science Foundation of China
Zou et al. (Fri,) studied this question.