Abstract

Cervical cancer remains a major global health burden, yet the molecular mechanisms driving its metabolic reprogramming are incompletely understood. Here, we identify heterogeneous nuclear ribonucleoprotein U (HNRNPU) as a novel non-histone substrate of lysine lactylation that links lactate accumulation to serine metabolism and tumor progression. We demonstrate that lactylation at lysine 181 (K181) stabilizes HNRNPU, enhances its binding to PHGDH mRNA, and maintains the exon 1-containing PHGDH transcript and mRNA stability, thereby sustaining PHGDH expression and activating the serine biosynthesis pathway. This metabolic rewiring promotes redox homeostasis, nucleotide synthesis, and cervical cancer cell proliferation both in vitro and in vivo. Mechanistically, we reveal a competitive interplay between lactylation and NAA50-mediated acetylation at K181, establishing a dynamic post-translational modification switch that fine-tunes HNRNPU function. Importantly, pharmacological inhibition of HNRNPU K181 lactylation by Pazopanib suppresses PHGDH expression and tumor growth, underscoring its translational potential. Collectively, our findings uncover a lactate-driven regulatory axis in which HNRNPU K181 lactylation integrates metabolic signaling with post-transcriptional regulation to promote cervical cancer progression, providing a promising therapeutic avenue for targeting metabolic vulnerabilities in malignancies.