Hsa_circ_0058495-mediated IGF2BP2 ubiquitination and m6A modification of MEKK1 promote the progression of PDAC

<b>Background</b>: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with dismal clinical outcomes. We identified hsa_circ_0058495 as significantly upregulated in PDAC tissues and PDAC cell-derived exosomes, where it contributes to tumor proliferation and invasion. The molecular mechanisms underlying its oncogenic function, however, remain incompletely understood. <b>Methods:</b> Differential circRNA expression was profiled by RNA sequencing. The functional role of hsa_circ_0058495 and its molecular interactions were interrogated through Western blotting, RT-qPCR, co-immunoprecipitation, RNA pull-down, and RNA immunoprecipitation assays. Confocal microscopy and PET/CT imaging were employed to delineate its biological effects <i>in vitro</i> and <i>in vivo</i>. <b>Results:</b> Hsa_circ_0058495 was enriched in PDAC-derived exosomes and stabilized IGF2BP2 by preventing TRIM25-mediated ubiquitination and attenuating autophagy-dependent degradation. Stabilized IGF2BP2 enhanced the stability of MEKK1 mRNA, leading to sustained ERK1/2 phosphorylation and consequent promotion of PDAC cell proliferation and invasion. Moreover, exosomal hsa_circ_0058495 facilitated M2 macrophage polarization, thereby fostering an immunosuppressive tumor microenvironment. <b>Conclusions:</b> Hsa_circ_0058495 promotes PDAC progression by stabilizing IGF2BP2 and activating the MEKK1-ERK signaling cascade, while exosomal transfer of hsa_circ_0058495 drives M2 macrophage polarization to reinforce tumor-associated immunosuppression. These findings establish hsa_circ_0058495 as a pivotal regulator of PDAC progression and underscore its potential utility as both a diagnostic biomarker and a therapeutic target.