Enhanced LDL uptake and PPARα signaling support OSCC cell survival under glutamine deprivation

Oral squamous cell carcinoma (OSCC) urgently requires innovative therapeutic strategies due to its severity and stagnant five-year survival rate. Targeting glutamine metabolism, a promising approach, is hampered by tumor cells' profound metabolic plasticity. Through a series of experiments, we uncovered heterogeneous responses of OSCC cell lines to glutamine deprivation: While most cells maintained growth, HSC3 cells showed a marked reduction in proliferation. Subsequent experiments have shown that this slowdown was not due to programmed cell death. Metabolomics and biochemical assays revealed elevated cholesterol ester (ChE) levels in glutamine-tolerant cells, not due to enhanced endogenous synthesis (HMGCS1/SQLE expression decreased) but via upregulated low-density lipoprotein receptor (LDLR)-mediated LDL uptake. Moreover, we found that fatty acid oxidation during glutamine deprivation not only supplied substrates for the tricarboxylic acid (TCA) cycle but also accelerated energy metabolism and potentially increased lipid synthesis for membrane structure and signaling. RNA sequencing identified robust enrichment of the peroxisome proliferator-activated receptor α (PPARα) pathway in tolerant cells. Reactive oxygen species (ROS) accumulation and activating transcription factor 5 (ATF5) nuclear translocation suggested the activation of multiple stress response pathways to maintain survival and growth under glutamine deprivation. Our study reveals a survival mechanism in OSCC: cells enhance exogenous lipid utilization to bypass glutamine dependence. Combined inhibition of LDL uptake and PPARα signaling may overcome metabolic plasticity, providing a rationale for precision therapies targeting metabolic heterogeneity in OSCC.