Epithelial SLC39A1 prevents acute lung injury through zinc-mediated transcriptional activation of autophagy in male mice.
Summary
SLC39A1 is upregulated in AT2 cells in male murine ALI and human ARDS. AT2-specific Slc39a1 deletion or zinc chelation worsened injury, while overexpression or zinc supplementation attenuated it; zinc could not rescue Slc39a1 deficiency. Mechanistically, zinc activates TFEB/TFE3/MITF to drive autophagy that protects AT2 cells, positioning SLC39A1 upstream of a protective zinc–autophagy pathway.
Key Findings
- SLC39A1 is highly upregulated in AT2 cells in male murine ALI and in patients with ARDS.
- AT2-specific Slc39a1 deletion or zinc chelation exacerbates lung injury; overexpression or zinc supplementation attenuates it.
- Zinc activates TFEB/TFE3/MITF to drive autophagy in AT2 cells; Lc3b or Tfe3 deficiency abolishes zinc protection, placing SLC39A1 upstream of autophagy.
Clinical Implications
Suggests biomarker-guided zinc supplementation or AT2-targeted enhancement of SLC39A1–TFEB/TFE3/MITF signaling in ARDS. Patient stratification by epithelial SLC39A1/autophagy status and sex may be necessary before clinical trials.
Why It Matters
This work defines a druggable epithelial zinc–autophagy axis with genetic epistasis and human relevance, clarifying when zinc supplementation could be protective and when it may fail.
Limitations
- Findings are preclinical and predominantly in male mice; sex-specific effects require confirmation.
- Clinical dosing, safety, and efficacy of zinc or pathway modulators in ARDS remain untested.
Future Directions
Validate in both sexes and diverse ARDS etiologies, develop AT2-targeted delivery, identify biomarkers of SLC39A1/autophagy activity, and initiate early-phase biomarker-enriched trials.
Study Information
- Study Type
- Basic/Mechanistic
- Research Domain
- Pathophysiology
- Evidence Level
- V - Preclinical mechanistic study using murine models and cellular systems.
- Study Design
- OTHER