Nuclear envelope rupture initiation in confined migration: A geometric-kinetic framework.

Nuclear envelope rupture during confined migration varies widely even at matched constriction size, indicating that pore diameter alone is an incomplete predictor of rupture initiation. This review proposes a geometric-kinetic framework that organizes rupture risk along two coupled axes. Geometric stress focusing is driven by high curvature at the leading nuclear apex, and rate-limited remodeling emerges when deformation outpaces effective nuclear relaxation. Each axis is captured by a measurable, workflow-anchored coordinate, placing diverse confinement events on a shared operating-point map. LINC complexes and perinuclear cytoskeletal assemblies are framed as candidate force-routing modules that shift these coordinates by modulating loading magnitude, mechanical buffering, and entry kinematics. Rupture initiation is explicitly separated from net nuclear damage, which also depends on repair kinetics and stress-response programs. Regime maps, a minimal measurement checklist, and falsifiable perturbation tests are provided to enable cross-platform calibration and generate testable hypotheses for cancer invasion, immune trafficking, and fibrotic remodeling.