Progerin cross-linking stiffens the nucleus and impairs mechanosensation in Hutchinson-Gilford progeria syndrome

Nuclear mechanosensation enables cells to detect and respond to mechanical cues through deformation governed by lamina and chromatin stiffness. In Hutchinson-Gilford Progeria Syndrome (HGPS), whether nuclear stiffening arises from progerin abundance alone and how it impacts mechanotransduction, remain unknown. Here we show that progerin-driven cross-linking is the primary mechanical determinant of nuclear stiffness, and that this excessive stiffening impairs mechanosensation. The Cross-linked Lamin Expression Factor (CLEF), combining lamin abundance and immobile fraction as orthogonal components, robustly predicts nuclear stiffness (r=0.84). Progerin aggregates tethered to the nuclear envelope induce persistent wrinkling resistant to hypotonic deformation, indicating stable mechanical anchoring. Strain mapping reveals that progerin spatial heterogeneity is a stronger local stiffness determinant than lamin A/C, and chromatin decompaction in HGPS makes progerin-rich lamina regions the dominant mechanical contributors. Excessive lamina cross-linking impairs YAP nuclear translocation across multiple independent perturbations of lamina mechanics, disrupting mechanosensation. These findings provide a mechanistic framework connecting nuclear architecture to defective mechanotransduction in laminopathies.