PSMD14-mediated PFKFB2 deubiquitination activates H3K27 lactylation to drive cancer stemness in gastric adenocarcinoma.

Deubiquitinases (DUBs) are pivotal in cancer progression, yet their role in metabolic reprogramming in gastric adenocarcinoma (GAC) remains unclear. Here, we discover that highly expressed PSMD14 strengthens tumor stemness and drives tumor progression by increasing glycolysis and lactate accumulation, which activates H3K27 lactylation (H3K27la) and turns to enhance the expression of PSMD14 and SOX9. Mechanistically, PSMD14 deubiquitinates PFKFB2 at K355, facilitating SCYL2-mediated phosphorylation of PFKFB2 at S466/S483, which increases the generation of fructose-2,6-bisphosphate, activating PFK1 and glycolysis. Additionally, the H3K27la/PSMD14/SCYL2/p-PFKFB2 axis correlates with increased glucose metabolic activity and poor prognosis in GAC patients. Notably, high-throughput screening of FDA-approved drugs reveals that Daclatasvir (DCV) exhibits high binding affinity for PSMD14 protein, disrupts the PSMD14-PFKFB2 interaction, reduces PFKFB2 activity and tumor burden. Collectively, our findings are the first to elucidate a positive feedback loop existing between PSMD14 and glycolysis in GAC progression, suggesting that PSMD14 blockade may represent a potential therapeutic approach for GAC.