BACE2 tunes lipid uptake through lipid transporters shedding supporting cancer cell proliferation

Lipids play crucial roles in signal transduction, membrane integrity, and energy metabolism. In cancer, lipid metabolism is frequently dysregulated. Proliferating cancer cells exhibit enhanced lipid uptake, synthesis, and storage; however, the molecular mechanisms driving cancer metabolic reprogramming remain poorly understood. In this study, we identify Beta-secretase 2 (BACE2), a sheddase overexpressed in several solid tumors, as a critical regulator of lipid metabolism, revealing novel pathways underlying cancer metabolic vulnerability. We employed a multi-omics approach, including global and spatial proteomics, lipidomics and N-terminomics, combined with advanced imaging and functional assays to dissect BACE2’s role in lipid regulation and cancer metabolism. Metabolomic analyses and fluorescent lipid analog tracking were used to assess BACE2’s impact on lipid uptake. Finally, functional experiments elucidated the causal relationship between BACE2-dependent lipid regulation and tumor cells proliferation. Analysis of patient tumor biopsies and cancer cell lines demonstrated a strong positive correlation between BACE2 expression, lipid metabolism, and lipid droplets (LDs) accumulation. Interestingly, extracellular lipid availability modulates BACE2 protein level, suggesting a feedback loop between lipid metabolism and BACE2 activity. Mechanistically, we proved that BACE2, assisted by the tetraspanin CD63, mediates the extracellular shedding of key lipid transporters, including the LDL receptor and the fatty acid transporter CD36, thereby tuning fatty acid and cholesterol uptake. BACE2 inhibition increased lipid influx, triggering the activation of PPAR-alpha signaling and LDs dynamics. In lipid-rich cancer cells this leads to lipolysis and metabolic stress, indicating that BACE2 activity is crucial for preventing lipolysis-induced damage. Inhibition of fatty acid uptake via CD36 blockade or suppression of ATGL-mediated lipolysis restores LDs integrity and rescues cell viability, underscoring BACE2’s role in maintaining a balanced lipid state critical for tumor cell survival and proliferation. Our findings uncover a novel function of BACE2 as a pivotal regulator of lipid transporter shedding, lipid uptake, and LDs homeostasis, ultimately shaping cancer cell metabolic adaptation and proliferation. These insights position BACE2 as a promising therapeutic target in lipid-addicted tumors, offering new avenues for cancer treatment.