The phase separation of ZC3H18 transcriptionally activates LDHA and forms lactylation-mediated positive feedback loop to promote tumorigenesis of lung cancer.

RNA-binding proteins (RBPs) play crucial roles in tumorigenesis and cancer treatment. As metabolic reprogramming is known to participate in tumorigenesis, elucidation of the mechanisms of crosstalk between RBPs and metabolism could provide new insights into cancer biology. Here, we found that the RBP ZC3H18 is overexpressed in lung cancer through copy number gain, which exerts oncogenic functions. Mechanistically, ZC3H18 undergoes phase separation to transcriptionally activate a key metabolic enzyme, lactate dehydrogenase A (LDHA), by binding to the LDHA promoter, thus promoting glycolysis and the production of lactate. The accumulation of lactate, in turn, activates the transcription of ZC3H18 through histone H3K18 lactylation (H3K18la) and directly induces the lactylation of ZC3H18 at the Lys186 residue (K186) in post-translational, thus forming a positive ZC3H18/LDHA/lactate/ZC3H18 feedback loop. Moreover, the combination of ZC3H18 inhibition and an LDHA small-molecule inhibitor (GSK2837808A) exhibited better antitumor efficacy in lung cancer patient-derived xenograft (PDX) model, suggesting the therapeutic potential of targeting the ZC3H18/LDHA axis. Taken together, our findings clarify the dialogue between RBP phase separation and lactate metabolism from a novel perspective and suggest that the ZC3H18/LDHA axis may serve as a potential therapeutic target for lung cancer.