Dietary Leucine Restriction Suppresses Platelet‐Driven HCC Growth by Attenuating mTOR Signaling

ABSTRACT

Platelets play a crucial role in regulating tumor progression, but the mechanisms underlying platelet‐induced metabolic reprogramming in hepatocellular carcinoma (HCC) remain incompletely understood. Here, metabolomic profiling identified significant accumulation of leucine in HCC cells following platelet incubation. Co‐culture with platelets promoted HCC cell proliferation, migration, and invasion in complete medium, whereas leucine deprivation in the co‐culture medium attenuated these malignant behaviors. Mechanistically, platelets selectively stimulated the phosphorylation of S6K1 and downstream S6, an activation that was suppressed under leucine‐deficient conditions. In addition, pharmacological inhibition of S6K1 activity using PF‐4708671 reduced platelet‐promoted cellular proliferation, migration, and invasion, confirming the S6K1/S6 axis as an essential functional effector of this response. In vivo, dietary leucine restriction reduced tumor growth following platelet pre‐incubation in the MHCC‐97H xenograft model. Together, these findings demonstrate that leucine accumulation and subsequent S6K1/S6 activation mediate platelet‐promoted HCC progression, indicating that targeting leucine availability or S6K1 signaling may offer therapeutic strategies for platelet‐associated HCC.