Valine availability controls oncogenic cell-cycle progression through translation of D-type cyclins

Although rapid proliferation of cancer cells imposes a heightened demand for specific amino acids, the mechanistic links between amino acid availability and cell cycle regulation remain poorly defined. Valine, a branched-chain amino acid, is traditionally recognized for its role in protein synthesis and energy metabolism, but its direct influence on malignant cell growth has not been established. Here, we identify intracellular valine as a critical regulator of oncogenic cell cycle progression. Across murine hepatocarcinoma, breast cancer, renal cancer, colorectal adenocarcinoma, valine deprivation triggered G₀/G₁ phase arrest and potently suppressed their proliferation. Mechanistically, valine depletion upregulated eukaryotic translation initiation factor 4E binding protein 1 (4E-BP1), which repressed cyclin D1 and D2 translation by sequestering eukaryotic translation initiation factor 4E (eIF4E). Concurrently, valine deprivation induced Sestrin2 expression and inhibited mammalian target of rapamycin (mTOR) activity, converging to attenuate mRNA translation. These findings uncover a previously unrecognized role of valine as a direct molecular controller of the cancer cell cycle, acting through translational repression of D-type cyclins. Targeting exogenous valine supply, in combination with cell cycle-directed therapies, may offer a promising strategy to suppress the growth of malignant tumors.