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Lactate controls activation of CDK1 by neddylation to promote mitosis transition in hypoxia

ABSTRACT: The G2/M transition is a highly energy-demanding processes in cell division, during which glycolysis-derived lactate metabolism provides a rapid energy supply. Lactate accumulation and the resulting hypoxic microenvironment have been implicated in tumor recurrence and therapy resistance. Here, we show that lactate markedly accumulates during the G2/M phase. This elevated lactate induces a high level of lactylation, which is associated with poor prognosis in patients with recurrent hepatocellular carcinoma (HCC). Mechanistically, we demonstrate that lactate-driven lactylation enhances the protein stability of the ubiquitin-conjugating enzyme E2 (UBE2M). UBE2M-mediated neddylation of CDK1 at the K20 site promotes the assembly of the CDK1-Cyclin B complex, thereby increasing CDK1 kinase activity to accelate G2/M transition. Moreover, neddylation-active CDK1 phosphorylates lactate dehydrogenase A (LDHA) at Thr74with lactate accumulation during the G2/M phase, a previously unrecognized modification that facilitates NADH regeneration and boosts lactate production. Consistently, mutation of the CDK1 neddylation site Lys20 attenuates LDHA phosphorylation and lactate generation. Finally, we identify theaflavin was a potent inhibitor of CDK1 neddylation that effectively sensitizes HCC to therapy. Collectively, our findings uncover a metabolic circuit in which neddylation couples with lactylation to rapidly meet energetic demands upon mitotic entry under tumor hypoxic conditions, suggesting a potential therapeutic strategy for cancer treatment.

ORGANISM(S): Homo Sapiens

SUBMITTER: Ping Xie

PROVIDER: PXD074677 | iProX | Thu Feb 12 00:00:00 GMT 2026

REPOSITORIES: iProX

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