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Simple Summary: Pancreatic cancer (PanCa) is one of the deadliest forms of cancer with limited therapeutic options. The available conventional therapies are highly toxic and often show resistance. Accumulating evidence suggests that dysregulated ribosome biogenesis has been linked to the survival and aggressive phenotypes of many tumor types, including PanCa. Thus, targeting ribosome biogenesis could be a novel approach for suppressing the growth of PanCa. The current study aimed to investigate the anti-cancer efficacy and underlying molecular mechanisms of honey against PanCa. Our results demonstrated that honey induces apoptosis and inhibits the growth and invasive potential of PanCa cells by targeting ribosome biogenesis components and c-Myc expression. This study suggests that honey can be used as an adjuvant along with conventional chemo/radiation therapy or immunotherapy for the management of PanCa. Pancreatic cancer (PanCa) is one of the deadliest cancers, with limited therapeutic response. Various molecular oncogenic events, including dysregulation of ribosome biogenesis, are linked to the induction, progression, and metastasis of PanCa. Thus, the discovery of new therapies suppressing these oncogenic events and ribosome biogenesis could be a novel therapeutic approach for the prevention and treatment of PanCa. The current study was designed to investigate the anti-cancer effect of honey against PanCa. Our results indicated that honey markedly inhibited the growth and invasive characteristics of pancreatic cancer cells by suppressing the mRNA expression and protein levels of key components of ribosome biogenesis, including RNA Pol-I subunits (RPA194 and RPA135) along with its transcriptional regulators, i.e., UBTF and c-Myc. Honey also induced nucleolar stress in PanCa cells by reducing the expression of various nucleolar proteins (NCL, FBL, and NPM). Honey-mediated regulation on ribosome biogenesis components and nucleolar organization-associated proteins significantly arrested the cell cycle in the G2M phase and induced apoptosis in PanCa cells. These results, for the first time, demonstrated that honey, being a natural remedy, has the potential to induce apoptosis and inhibit the growth and metastatic phenotypes of PanCa by targeting ribosome biogenesis. [ABSTRACT FROM AUTHOR]