LRP8-dependent cholesterol metabolism modulates mTORC1 signaling and apoptotic pathways in multiple myeloma

Cholesterol plays a crucial role in tumor metabolism. Studies have shown that the serum cholesterol level of multiple myeloma (MM) patients significantly decreases, probably owing to the augmented uptake by MM cells. Despite its significance for MM, research on its metabolism within MM is limited. Our analysis of clinical data from 703 newly diagnosed MM patients revealed that low serum cholesterol is associated with poor prognosis, and it stems from the elevated cholesterol consumption by MM cells. By exploring the transcriptome and single-cell RNA-seq data of patients with different cholesterol levels in our center, we identified LRP8 as a key regulator of cholesterol metabolism in MM, which is closely related to prognosis and disease stages. We verified the oncogenic role of LRP8 in vitro and in vivo. Knockdown of LRP8 can facilitate apoptosis and cell cycle arrest in MM cells. Meanwhile, we employed mouse xenograft tumor model to replicate the phenomenon that MM cells with high LRP8 expression consume cholesterol, causing low serum cholesterol. Mechanistically, high LRP8 expression enhances cholesterol utilization and uptake by MM cells; LRP8 inhibition reduces cholesterol absorption, further weakening the activity of the cholesterol-dependent mTORC1 pathway in MM cells and inducing apoptosis. Concurrently, it triggers an upregulation of protective autophagy. Further suppression of autophagy can lead to extensive apoptosis of MM cells. Our study reveals that LRP8 regulates cholesterol metabolism in MM cells and influences the processes of cell apoptosis and autophagy through metabolic-related pathways. LRP8 holds potential as a therapeutic target for MM.