Fatty acid 2-hydroxylation restrains gastric cancer by blocking CD36 palmitoylation and fatty acid uptake.

Fatty acid (FA)-induced internalization of the FA transporter CD36 normally functions as an intrinsic brake on FA uptake and lipid overload, but cancer cells can bypass this checkpoint to sustain lipid-fueled growth. The mechanism underlying this failure remains unclear. Here, we identify a FA 2-hydroxylase (FA2H)-CD36 signaling axis that operates as an endogenous brake on lipid fueling in gastric cancer cells. FA2H-derived (R)-2-hydroxy palmitic acid ((R)-2-OHPA) disrupts CD36 interaction with its palmitoyltransferase DHHC4, thereby limiting CD36 palmitoylation and trafficking to the plasma membrane. Loss of FA2H permits CD36 palmitoylation and establishes a feed-forward loop that amplifies FA uptake, lipid accumulation, and tumor growth. Restoring FA2H expression or supplementing cells with exogenous (R)-2-OHPA reinstates the lipid-sensing checkpoint. Moreover, FA2H activation sensitizes gastric cancer cells to inhibition of endogenous FA synthesis through blockade of FA synthase (FASN) or stearoyl-CoA desaturase 1 (SCD1). In vivo, (R)-2-OHPA treatment or expression of the palmitoylation-deficient CD36 AASS mutant attenuates FA2H deficiency-driven lipid accumulation and tumor growth, positioning CD36 palmitoylation as the critical effector in this metabolic circuit. Together, these findings establish FA 2-hydroxylation as a metabolic checkpoint that links FA structure to CD36 trafficking and FA utilization in gastric cancer, revealing a targetable vulnerability in lipid-driven tumor growth.