Cross-species transcriptomics identify mineralocorticoid receptor pathway overactivation as a central driver of ocular rosacea

Abstract Ocular rosacea (OR) is a chronic inflammatory disease of the ocular surface frequently associated with meibomian gland dysfunction (MGD), with limited therapeutic options and an underexplored pathophysiology. Here, we uncover the pivotal role of mineralocorticoid receptor (MR) pathway overactivation in driving MGD and OR. Analysis of eyelid tissues from OR patients revealed increased MR expression and altered local corticosteroid metabolism, associated with inflammation, fibrosis, and impaired meibocyte renewal. Using a transgenic rat model overexpressing human MR, we demonstrate that MR overactivation initiates subclinical MGD and, with aging or ultraviolet-B exposure, drives a full OR-like phenotype characterized by gland dropout, oxidative and mitochondrial stress, immune infiltration, epithelial barrier disruption, and secondary corneal damage. Cross-species transcriptomic integration of rat, human MGD, and rosacea datasets identified a conserved MR-dependent gene signature, highlighting S100A9 as a specific downstream target and biomarker of MR activation. Local pharmacological MR antagonism suppressed S100A9 expression. These findings establish MR overactivation as a unifying pathogenic driver of MGD and OR and identify MR blockade as a promising therapeutic strategy, with S100A9 as a candidate biomarker for patient stratification and treatment monitoring.