Abstract

Hepatocellular carcinoma (HCC) exhibits diminished capacity for oxidative utilization of long-chain fatty acids (LCFAs). However, the strategic and mechanistic basis by which HCC cells enact metabolic reprogramming to adapt to impaired LCFAs oxidation and sustain viability remains incompletely defined. Here we report that solute carrier family 27 member 5 (SLC27A5), the specific transporter for LCFAs, is broadly downregulated in HCC cells, resulting in reduced LCFAs uptake. In HCC cells with impaired LCFAs oxidation, diminished LCFAs import caused by SLC27A5 loss does not lead to energy deficiency, but instead prevents lipotoxicity derived from unutilized LCFAs, thereby supporting HCC cell growth. Impaired LCFAs oxidation suppresses peroxisome proliferator-activated receptor alpha (PPAR-α) signaling, which in turn represses SLC27A5 transcription, accounting for the widespread downregulation of SLC27A5 in HCC. Owing to reduced LCFAs uptake, HCC cells with low SLC27A5 rely on the glutamine reductive pathway for fatty acid biosynthesis to maintain total fatty acid levels, rendering these cells highly sensitive to glutaminase inhibition. In conclusion, we demonstrate that SLC27A5 downregulation represents a response to defective LCFAs oxidation in HCC, and reduced LCFAs uptake consequent to low SLC27A5 expression constitutes a survival adaptation that enables HCC to tolerate impaired LCFAs oxidation. Glutaminase inhibitors may serve as a precision therapeutic strategy for HCC characterized by low SLC27A5 expression.