PDP1 drives hepatocellular carcinoma progression by regulating senescence through the cAMP/Ca²⁺ signaling pathway

Hepatocellular carcinoma (HCC) is a lethal malignancy with limited therapeutic options. Cellular senescence exerts a critical role in tumor progression, but the regulatory mechanisms remain unclear. This study investigates the role of pyruvate dehydrogenase phosphatase 1 (PDP1) in modulating senescence-associated malignant progression in HCC. Our study suggests that PDP1 is upregulated in patients with HCC and is significantly associated with poor prognosis. Functionally, PDP1 induces cellular senescence, activates cyclic adenosine monophosphate (cAMP)/Ca²⁺ signaling, and promotes senescence-associated secretory phenotype (SASP)-driven epithelial-mesenchymal transition (EMT), stemness, and malignant progression. Xenograft models further demonstrate that PDP1 enhances tumor growth in vivo, accompanied by activation of senescence-associated pathways, including p16, p21, cAMP, and Ca²⁺. Adenylyl cyclase 5 (ADCY5), a membrane-associated enzyme responsible for catalyzing ATP into cAMP, is identified as a critical downstream mediator of these effects and serves as a major source of intracellular cAMP production. Mechanistically, PDP1 suppression enhances glycolysis and histone H3 lysine 18 lactylation (H3K18la), a recently identified lactate-derived epigenetic modification, leading to activation of DNA methyltransferase 1 (DNMT1), the primary enzyme maintaining DNA methylation patterns, and subsequent ADCY5 promoter hypermethylation and transcriptional silencing. Importantly, glycolysis inhibition restores senescence and reverses PDP1-driven malignant phenotypes. Collectively, these findings identify that PDP1 drives senescence-associated malignant progression in HCC by linking glycolytic regulation, histone lactylation, and DNA methylation to the control of ADCY5 expression and subsequent cAMP/Ca²⁺ signaling, underscoring its potential as a therapeutic target.