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Background  Patients with lymph node (LN)-positive pancreatic ductal adenocarcinoma (PDAC) have extremely poor survival rates. Circular RNAs (circRNAs), a newly discovered type of endogenous noncoding RNAs, have been proposed to mediate the progression of diverse types of tumors. However, the role and underlying regulatory mechanisms of circRNAs in the LN metastasis of PDAC remain unknown.    Methods  Next-generation sequencing was used to identify differentially expressed circRNAs between PDAC and normal adjacent tissues. In vitro and in vivo experiments were conducted to evaluate the functional role of circNFIB1. RNA pulldown and luciferase assays were performed to examine the binding of circNFIB1 and miR-486-5p.    Results  In the present study, we identified that a novel circRNA (circNFIB1, hsa_circ_0086375) was downregulated in PDAC and negatively associated with LN metastasis in PDAC patients. Functionally, circNFIB1 knockdown promoted lymphangiogenesis and LN metastasis of PDAC both in vitro and in vivo. Mechanistically, circNFIB1 functioned as a sponge of miR-486-5p, and partially reversed the effect of miR-486-5p. Moreover, circNFIB1 attenuated the oncogenic effect of miR-486-5p and consequently upregulated PIK3R1 expression, which further downregulated VEGF-C expression through inhibition of the PI3K/Akt pathway, and ultimately suppressed lymphangiogenesis and LN metastasis in PDAC.    Conclusions  Our findings provide novel insight into the underlying mechanism of circRNA-mediated LN metastasis of PDAC and suggest that circNFIB1 may serve as a potential therapeutic target for LN metastasis in PDAC.    Graphical abstract

circNFIB1 inhibits lymphangiogenesis and lymphatic metastasis via the miR-486-5p/PIK3R1/VEGF-C axis in pancreatic cancer