Inducing oxidative stress by targeting the cholesterol biosynthesis pathway augments the efficacy of bortezomib in multiple myeloma.

Proteasome inhibitors, particularly bortezomib (BTZ) which induces oxidative stress, remain the cornerstone of multiple myeloma (MM) therapy. However, resistance driven by metabolic reprogramming and redox adaptation limits their long-term efficacy. Here, we identify a cholesterol biosynthesis-dependent antioxidant mechanism that shields MM cells from BTZ-induced generation of reactive oxygen species (ROS). High cholesterol biosynthesis activity characterizes BTZ-nonresponsive plasma cells and correlates with poor prognosis. Genetic silencing of SREBF2, the master transcriptional regulator of cholesterol metabolism, sensitized MM cells to BTZ both in vitro and in vivo. Pharmacological inhibition of HMG-CoA reductase, the rate-limiting enzyme of cholesterol biosynthesis, with the clinically approved atorvastatin likewise enhanced the anti-myeloma activity of BTZ in vitro and in vivo. Mechanistically, the lipid raft protein FLOT1 promoted FOXO3 nuclear translocation and SREBF2 activation, thereby driving increased cholesterol biosynthesis and accumulation of the intermediate metabolite 7-dehydrocholesterol (7-DHC), a critical antioxidant that mitigated BTZ-induced cytotoxicity. Decreasing 7-DHC production by disrupting SREBF2 activation or treating with atorvastatin impaired the cellular ROS detoxification capacity and enhanced BTZ-induced cytotoxicity. Collectively, our findings identify that MM cells resist therapy-induced ROS by accumulating 7-DHC through activation of cholesterol biosynthesis, and provide preclinical evidence for repurposing statins to augment the efficacy of BTZ therapy.