Dual targeting PPARα and NPC1L1 metabolic vulnerabilities blocks tumorigenesis

Herein we identified Niemann–Pick C1-like 1 (NPC1L1) as a downstream effector of PKM2. Knockout of PKM2 enhanced NPC1L1 expression in breast cancer cells, while reducing the peroxisome proliferator-activated receptor α (PPARα) signaling pathway. Fenofibrate, a PPARα agonist, promoted NPC1L1 expression. Combined administration of fenofibrate and ezetimibe, a NPC1L1 inhibitor, significantly induced cytoplasmic vacuolation and cell apoptosis. Mechanistically, combined administration activated the inositol required enzyme 1α(IRE1α)- x box binding protein spliced (XBP1s) and lysine demethylase 6B (KDM6B). XBP1s interacted with KDM6B to activate genes involved in unfold protein response through demethylating di- and tri-methylated lysine 27 of histone H3 (H3K27) and consequentially increasing the level of H3K27 acetylation in breast cancer cell lines. Fenofibrate and ezetimibe synergistically inhibited tumor growth and lung metastasis in vivo. Together, our findings reveal that dual targeting PPARα and NPC1L1 may be developed as a new regimen for breast cancer therapy.