Clinical assessment of biochemical and biomechanical remodeling of the human lens during cataract progression

Cataract formation is accompanied by progressive alterations in lens biomechanics and protein composition; however, the integrated relationship between biochemical remodeling and mechanical stiffening remains incompletely understood. Clarifying this relationship is essential for identifying biochemical features associated with cataract progression beyond descriptive clinical changes. In this observational cross-sectional study, human lenses spanning normal to advanced cataract grades were analyzed using quantitative ultrasound elastography to determine apparent Young’s modulus. Biochemical composition was assessed by quantifying water-soluble, urea-soluble, insoluble, and yellow protein fractions, along with water content. Multivariate compositional regression identified the CLR-transformed water-soluble protein component as the variable showing the strongest individual adjusted association with apparent stiffness. Lens stiffness increased significantly with cataract severity, with advanced cataract lenses exhibiting markedly higher Young’s modulus values. Biochemical analysis revealed a grade-dependent reduction in water-soluble protein and hydration, accompanied by accumulation of aggregated and yellow protein fractions. Multivariate regression identified the CLR-transformed water-soluble protein component as the variable showing the strongest adjusted association with apparent stiffness. PCA captured 88.1% of total variance within the first two components, defining a coupled biochemical–biomechanical axis of cataract progression. Lenses followed a continuous trajectory from normal to advanced states, with significant clustering by grade (PERMANOVA, p = 0.001). Cataract progression is characterized by coordinated biochemical and biomechanical remodeling of the lens. Protein insolubilization and reduced hydration were independently associated with increased lens stiffness. This integrated framework provides a basis for interpreting elastography measurements and provides a quantitative framework for investigating biomechanics-informed markers of cataract progression.