Daily Ards Research Analysis

Zinc transporters regulate intracellular zinc homeostasis, but their role in acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) remains underexplored. Here, we show that the zinc transporter SLC39A1 is highly upregulated in alveolar type II (AT2) cells from male murine ALI models and patients with ARDS. AT2-specific Slc39a1 deletion or zinc chelation exacerbates lung injury, whereas overexpression or zinc supplementation attenuates it. Notably, zinc supplementation fails to rescue Slc39a1-deficient mice, indicating SLC39A1 governs zinc uptake to control ALI. Zinc likely directly binds to and activates TFEB, TFE3, and MITF, inducing transcriptional activation of autophagy to eliminate damaged mitochondria and suppress apoptosis/pyroptosis in AT2 cells. Lc3b- or Tfe3-deficient mice show heightened lung injury, which remain unmitigated by zinc supplementation. Importantly, administration of AAV-shLc3b to AT2 Slc39a1-deficient mice did not further aggravate lung injury beyond that caused by either intervention alone. This epistatic relationship places SLC39A1 upstream of autophagy activation within a linear pathway. Collectively, we define an essential role for epithelial SLC39A1 in host defense against ALI/ARDS, which is mediated by a protective zinc-autophagy axis.

Endothelial barrier dysfunction and consequent vascular injury are central contributors to acute lung injury (ALI) during sepsis. However, the underlying mechanisms remain incompletely understood, and effective therapeutic strategies targeting endothelial repair are still lacking. Here, we identify that intracellular leucine-rich α2-glycoprotein 1 (LRG1) in endothelial cells (EC) is significantly upregulated and directly promotes the degradation of vascular endothelial cadherin (VE-cadherin), a core adherens junction protein essential for maintaining vascular barrier integrity in septic ALI. Mechanistically, LRG1 recruits the E3 ubiquitin ligase membrane-associated ring-CH-type finger 2 (MARCH2) to catalyze K48-linked polyubiquitination of VE-cadherin at lysine 633, leading to its proteasomal degradation and subsequent endothelial barrier disruption. Genetic deletion of Lrg1 or pharmacological intervention with a proteolysis targeting chimera (PROTAC)-based degradation strategy significantly reduced VE-cadherin loss, alleviated endothelial hyperpermeability, and mitigated ALI in septic mice. Collectively, our study elucidates a previously unrecognized role of endothelial LRG1 in disrupting EC adherens junctions, providing novel insights into the pathogenesis of sepsis-associated injury and proposing a potential therapeutic strategy for sepsis-induced ALI and acute respiratory distress syndrome (ARDS).

Acute respiratory distress syndrome (ARDS) is a high-mortality lung disorder driven by excessive neutrophil activation. While neutrophils are central to ARDS, the metabolic pathways fueling their inflammatory response remain unclear. This study identifies CD177 as a critical regulator of neutrophil glycolysis and NLRP3 inflammasome activation. Bioinformatics and animal models show that elevated CD177 correlates strongly with increased lactate and IL-1β levels. In vitro experiments demonstrate that CD177 knockdown reduces glycolytic flux and suppresses IL-1β release, a process reversed by lactate supplementation. Furthermore, treating ARDS mice with anti-CD177 antibodies significantly reduces pulmonary edema and tissue injury. These results establish the CD177-glycolysis-NLRP3 axis as a major driver of lung inflammation. Targeting this metabolic checkpoint provides a promising strategy for treating ARDS.