Sexual dimorphism shapes AAK trajectory in Pax6 deficiency mouse model with early immune activation, impaired innervation, and altered tears

Sex emerges as a potent modifier: in otherwise modestly dimorphic wild-type corneas, Pax6 haploinsufficiency drives male- and female-specific gene networks that converge on inflammation and extracellular-matrix remodeling but diverge in metabolic and innate-immune programs; tears mirror and likely reinforce these shifts, with female-biased hyposecretion at baseline and, after abrasion, a failure of Pax6+/− tears to mount the ribosome/translation and axon-guidance response seen in controls, instead exaggerating innate-immune and keratinization pathways.

Together, the data recast AAK as a vicious cycle of epithelial dysmaturation, chronic inflammation, and neurotrophic failure amplified by sex-modulated lacrimal changes. By pinpointing early inflammatory priming, a cornea-encoded denervation mechanism, and modifiable tear-film deficits, this work nominates tractable entry points, tempering inflammation, restoring neurotrophic support and reinnervation, and normalizing tear quality, with direct translational relevance to preventing or slowing AAK.