mTOR inhibition reprograms cellular lipid homeostasis by inducing alternative lipid uptake and promoting cholesterol transport.

The mechanistic target of rapamycin (mTOR) is a key regulator of lipid homeostasis by controlling processes including lipid uptake and biosynthesis. mTOR dysregulation and consequent altered lipid metabolism are common in various diseases, including cancers, making mTOR a promising therapeutic target. Therefore, it is crucial to understand how mTOR activation and inhibition reprogram lipid homeostasis. In human cancer cell lines, mTOR inhibition induces alternative lipid uptake through translation eukaryotic initiation factor 3D (eIF3D)-mediated low-density lipoprotein receptor (LDLR)-related protein 6 (LRP6) increase and activates liver X receptor β (LXRβ), promoting cholesterol release from lysosomes and its transport to the plasma membrane via Niemann-Pick disease type C (NPC) intracellular cholesterol transporter 1 (NPC1). This signaling supports tumor cell survival and stress resistance. In mouse xenograft models, combining mTOR inhibition with LRP6 knockdown or NPC1 targeting significantly suppresses tumor growth. Our findings highlight mTOR feedback signaling in reprogramming lipid homeostasis and its therapeutic potential to treat diseases characterized by dysregulated mTOR.