The mtROS-Stat1 Axis Defines an Acinar Dysfunctional State Linking Metabolic Stress to Immune Activation in Cigarette Smoking-Associated Dry Eye Disease.

PURPOSE: Dry eye disease (DED) is a prevalent ocular disorder in which environmental factors, particularly cigarette smoking (CS), are increasingly implicated. However, the underlying mechanisms remain poorly defined.

METHODS

We integrated cross-sectional data from the UK Biobank with a chronic CS-exposure mouse model and single-nucleus RNA sequencing of the lacrimal gland (LG) tissue. Histological and functional assays were used to characterize ocular surface and LG phenotypes. Transcriptomic analyses were conducted to resolve acinar cell states, define metabolic and inflammatory pathways, and infer cell-cell interactions. Pharmacological interventions targeting mitochondrial reactive oxygen species (mtROS) and Stat1 signaling were applied to assess therapeutic potential.

RESULTS

CS was identified as an independent, dose-dependent risk factor for DED and induces progressive LG dysfunction characterized by corneal damage and impaired tear secretion. Single-cell profiling revealed a damage-associated acinar cell (DAAC) state marked by loss of secretory identity and acquisition of an immunogenic phenotype. Mechanistically, we show that mitochondrial oxidative phosphorylation suppression eventually activates Stat1 signaling, which functions as a stress-responsive metabolic checkpoint driving the transition of acinar cells into the DAAC state. Functionally, DAACs exhibited enhanced antigen presentation and actively engage immune cells, supporting an epithelial-driven inflammatory model of DED. Targeting either mtROS or Stat1 ameliorated acinar dysfunction, suppress immune activation, and restored tear secretion.

CONCLUSION

These findings define a mtROS-Stat1-DAAC axis that links metabolic stress to epithelial dysfunction and immune activation in CS-associated DED. This work provides a mechanistic framework connecting environmental exposure to tissue pathology and highlights potential therapeutic strategies for intervention.