β-catenin loss drives nuclear lamina aging through enhancer dysfunction and β-TrCP-mediated proteostasis

Nuclear lamina dysfunction is a hallmark of aging, yet its upstream drivers remain unclear. Here, we identify β-catenin loss as a central driver of nuclear lamina deterioration and cellular senescence. Using primary fibroblasts derived from base-edited non-human primate models of Hutchinson-Gilford progeria syndrome (HGPS) and from physiologically aged non-human primates, together with skin tissue validation from HGPS model animals, we show that β-catenin depletion is sufficient to induce nuclear abnormalities and proliferative arrest. Mechanistically, β-catenin is suppressed by a dual-layer regulatory program involving enhancer dysfunction that reduces CTNNB1 transcription and β-TrCP-mediated proteasomal degradation that limits protein abundance. Notably, β-TrCP undergoes subcellular redistribution in HGPS and physiologically aged non-human primate fibroblasts. Restoration of β-catenin activity via WNT3A stimulation, small-molecule activation, or CTNNB1 overexpression rescues nuclear architecture and reinstates proliferative capacity. Together, these findings link chromatin regulation and proteostasis to nuclear lamina integrity during aging.