Ruxolitinib inhibits CaMKII-γ to reverse bortezomib resistance in multiple myeloma

Multiple myeloma (MM) is the second most common hematologic malignancy, with increasing incidence and earlier onset. Despite the therapeutic efficacy of proteasome inhibitors and other strategies, nearly all patients eventually develop resistance, making the discovery of novel drug targets and innovative therapeutic approaches an urgent clinical need. A critical knowledge gap exists regarding the molecular mechanisms underlying bortezomib (first-line MM drug) resistance, which hinders the development of effective resistance-reversing strategies. Here we show calcium/calmodulin-dependent protein kinase II gamma (CaMKII-γ) regulates bortezomib-resistant MM (BRMM) via AMPK-ULK1-autophagy axis. High-throughput screening identified ruxolitinib as a selective CaMKII-γ inhibitor, which reverses BRMM resistance in vitro (using U266 and KMS11 bortezomib-resistant cell lines) and in vivo (using female BALB/c nude mouse model), with efficacy comparable to genetic CaMKII-γ ablation, providing a potential therapeutic strategy for BRMM with broader implications to improve patient outcomes in the future.