GMPS drives pancreatic cancer progression via suppressing DNA damage, STING activation and cellular senescence

Background Pancreatic ductal adenocarcinoma (PDAC) is an extremely aggressive malignancy with scarce viable treatment targets. Metabolic rewiring is a typical characteristic of PDAC, but the roles of many metabolic enzymes remain poorly defined. Methods We integrated DepMap and TCGA data to screen metabolic genes essential for PDAC proliferation and poor prognosis. Expression patterns were validated by immunohistochemistry and western blotting in 97 PDAC tissues and multiple cell lines. Genetic manipulation experiments in PDAC cell lines, organoids, and a patient‑derived xenograft model were performed to assess proliferation and tumor growth. RNA sequencing, proteomics, flow cytometry, SA-β-gal staining, and immunofluorescence were used to investigate underlying mechanisms. Results Among 2752 metabolic genes, GMPS had the highest hazard ratio and its high expression correlated with worse prognosis. GMPS-high tumors showed increased mutation frequencies of KRAS and TP53, while GMPS-low tumors had higher immune infiltration and drug sensitivity. GMPS protein was elevated in PDAC tissues and cell lines (MIA PaCa-2, Capan-1). GMPS knockdown reduced colony formation, proliferation, organoid growth, and PDX tumor growth, whereas overexpression promoted organoid expansion. Mechanistically, GMPS knockdown induced DNA damage (γH2AX⁺ cells), G1 phase arrest, cellular senescence (upregulation of IL6, MMP2, p21, and increased SA-β-gal staining), and activated the STING-TBK1 pathway. Conclusions GMPS drives PDAC proliferation by suppressing senescence and STING signaling. GMPS is a promising therapeutic target and prognostic biomarker in PDAC.