3-Hydroxyacyl-CoA dehydratase 2 (HACD2), an obesity-related gene involved in the elongation of long-chain fatty acids, is highly expressed in pancreatic cancer (PC) and is associated with patient prognosis. Interestingly, the study reveals that HACD2 mediated the proliferation of PC cells in a dehydratase-independent manner, affecting the downstream glycolytic pathway. Mechanistically, HACD2 promotes PC cells proliferation by binding to E3 ubiquitin-protein ligase parkin (PRKN) and enhancing pyruvate kinase PKM (PKM2) dissociation from PRKN, resulting in reduced ubiquitination of PKM2 and increased dimerization of PKM2, which subsequently promote c-Myc expression and tumor growth. Moreover, HACD2 overexpression-induced PC growth is mitigated by knockdown of PKM2 or overexpression of PRKN. Furthermore, the weight loss drug orlistat, which potentially binds to HACD2, disrupted the interaction between HACD2 and PRKN and further increased the ubiquitination of PKM2. Therefore, this study elucidates the mechanism by which the obesity-related gene HACD2 regulates PC cells proliferation through a noncanonical signaling pathway, which may provide a potential new target and strategy for the individualized clinical treatment of PC.