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

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.