Targeting KPNA2 Enhances Bortezomib Anti-myeloma activity Through Suppressing Non- Canonical NF-κB-Mediated Autophagy in Multiple Myeloma

Bortezomib (BTZ)-based therapy has substantially improved clinical outcomes in multiple myeloma (MM), the emergence of BTZ resistance remains a major obstacle to achieving durable disease control. Although autophagy-mediated proteotoxic stress adaptation has been implicated in modulating cellular responses to BTZ, the upstream regulators that orchestrate this adaptive process and their contribution to BTZ sensitivity remain poorly understood. In this study, we identify karyopherin α2 (KPNA2), a critical nucleocytoplasmic transport receptor, as a previously unrecognized regulator of BTZ sensitivity in MM. Integrated analysis of public datasets and clinical samples demonstrated that KPNA2 expression is significantly elevated during MM progression and independently predicts inferior survival. Functional investigations revealed that KPNA2 promotes MM cell proliferation and resistance to BTZ-induced apoptosis. Mechanistically, KPNA2 selectively activates the non-canonical NF-κB pathway, promoting p100 processing and nuclear accumulation of p52/RelB, which subsequently enhances autophagic activity and establishes a protective stress-adaptation program. Genetic depletion or pharmacological inhibition of KPNA2 suppresses this signaling cascade, inhibits autophagy, and enhances BTZ sensitivity in vitro and in vivo . Collectively, our findings establish KPNA2 as a molecular bridge linking nuclear transport machinery with alternative NF-κB signaling and autophagy-dependent proteostasis. Targeting the KPNA2/non-canonical NF-κB/autophagy axis represents a promising therapeutic strategy for enhancing BTZ sensitivity and treatment responses in MM.