Title : Targeting SIRT7-Mediated DNA damage repair as a novel strategy in pancreatic cancer

Background: Pancreatic cancer is a highly lethal malignancy characterized by poor prognosis and limited therapeutic options. Recent evidence suggests that Sirtuin 7 (SIRT7), a nucleolar NAD?-dependent deacetylase, plays an oncogenic role in multiple cancers; however, its precise function and therapeutic relevance in pancreatic cancer remain insufficiently explored.

Methods: We integrated public datasets and clinical samples to examine SIRT7 expression and prognosis in pancreatic cancer. Gain- and loss-of-function assays in vitro and in vivo were conducted to assess its biological role. DNA damage repair kinetics, homologous recombination (HR) reporter assays, and RAD51 expression analyses were employed to delineate the mechanistic link between SIRT7 and DNA damage response (DDR). Furthermore, structure-based virtual screening, molecular docking, and dynamics simulations were performed to identify and prioritize candidate SIRT7 inhibitors, which were subsequently validated by biochemical and functional assays.

Results: SIRT7 was markedly overexpressed in pancreatic cancer tissues and cell lines, with high expression significantly associated with adverse prognosis. Functionally, SIRT7 enhanced tumor proliferation both in vitro and in vivo by facilitating HR-mediated DNA damage repair. Mechanistically, SIRT7 promoted RAD51 accumulation and accelerated DDR kinetics, whereas SIRT7 depletion impaired repair efficiency and increased DNA damage sensitivity. Virtual screening identified HIT213729655 as a potent candidate inhibitor with favorable pharmacological properties. HIT213729655 demonstrated high-affinity binding to the active site of SIRT7, confirmed by molecular dynamics simulations and Cellular Thermal Shift Assays. Functionally, it suppressed SIRT7-dependent HR repair, induced sustained DNA damage, and exerted strong cytotoxic effects in pancreatic cancer cells, surpassing existing SIRT7 inhibitors.

Conclusions: Our findings establish SIRT7 as a critical driver of pancreatic carcinogenesis through enhancement of HR-mediated DNA repair. We identify HIT213729655 as a selective and efficacious SIRT7 inhibitor, offering a promising therapeutic strategy to overcome chemoresistance in pancreatic cancer.

Jianghao Ren is a Ph.D. candidate specializing in pancreatic cancer research. His work focuses on the molecular mechanisms of tumor progression, particularly the role of DNA damage repair pathways in carcinogenesis and therapeutic resistance. He has conducted studies integrating bioinformatics, cellular models, and in vivo experiments to investigate novel oncogenic drivers and therapeutic targets. His recent research highlights the oncogenic function of SIRT7 in pancreatic cancer and explores its therapeutic potential through selective inhibition, aiming to provide a foundation for new strategies against this lethal malignancy.