Axial elongation is associated with stress-dominant aqueous humour proteomic changes in eyes with and without open-angle glaucoma

Background/aims Axial elongation is associated with increased susceptibility to ocular disease, including glaucoma yet the underlying molecular changes remain poorly defined. We investigated whether axial length is associated with aqueous humour proteomic changes, reflecting altered stress signalling and impaired regulatory or survival-related pathways. Methods This cross-sectional study included aqueous humour samples from 19 eyes (13 stable open-angle glaucoma and 6 controls) undergoing cataract surgery. Proteomic profiling was performed using the Olink Reveal platform. After quality control, 1034 proteins were analysed. Associations between axial length and normalised protein expression were assessed using multivariable linear regression adjusted for age, sex and disease status, with additional permutation and sensitivity analyses. Results Thirty-eight proteins showed nominal associations with axial length. Although no proteins met false discovery rate thresholds, the nominal associations suggested a directional pattern. Longer axial length was nominally associated with higher expression of stress-related proteins (LIF, IL11, CHUK) and lower expression of regulatory and cell survival-related proteins (XIAP, STAT2, DAPP1, COMMD9). XIAP showed an inverse association and LIF a positive association, exemplifying a shift towards stress-dominant signalling. Several candidate proteins showed consistent associations in the stable glaucoma subgroup. Conclusion Exploratory protein-level associations with axial length suggested a possible shift towards increased stress-related and reduced regulatory or survival-related signalling. As no associations survived multiple-testing correction, these findings should be considered hypothesis-generating and require validation in larger independent cohorts.