Collectively, our data reveal a novel mechanism by which circEPB41L2 regulates glycolytic metabolism and EMT to inhibit NSCLC development and metastasis via binding to the RRM1 domain, the crucial motif of an RNA-binding protein for the ubiquitination by TRIP12, which reduces PKM2 and Vimentin expression but enhances PKM1 and E-cadherin expression. The gene discussed is PKM; the disease is non-small cell lung carcinoma.