Nicotinamide riboside enhances the efficacy of gemcitabine and suppresses PDAC premalignant lesions via SIRT3 activation.

Pancreatic ductal adenocarcinoma (PDAC) remains a lethal malignancy with limited therapeutic options. This study identifies nicotinamide riboside (NR), a natural NAD+ precursor, as a dual-function agent that enhances chemosensitivity and suppresses tumor progression by activating the mitochondrial deacetylase sirtuin 3 (SIRT3). Multi-level clinical analyses revealed progressive SIRT3 downregulation in PDAC pathogenesis, correlating with poor survival. Genetic ablation of SIRT3 accelerated premalignant lesions in spontaneous models, whereas NR administration restored SIRT3 expression and activated its mitochondrial regulatory network, comprising key metabolic enzymes and respiratory chain components, in a SIRT3-dependent manner. In spontaneous PDAC models, NR monotherapy delayed carcinogenesis by suppressing the progression of premalignant lesions. Moreover, NR significantly potentiated gemcitabine efficacy both in vitro and in subcutaneous PDAC models, demonstrating synergistic enhancement of chemotherapy-induced tumor cell death. These findings establish NR as a promising SIRT3-targeting adjuvant that both enhances the efficacy of standard chemotherapy and delays carcinogenesis, thereby overcoming therapeutic resistance in established PDAC and potentially impeding its development.