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 (a farnesylated variant form of lamin A) 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. We introduce a parameter called the cross-linked lamin expression factor (CLEF), which combines lamin abundance and immobile fraction as orthogonal components, and 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 (also known as YAP1) 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.