In our study, LC/MS revealed PKM2 as a new binding partner of ARHGAP24 and showed that it could recruit WWP1, an E3 ligase, to promote ubiquitination as well as proteasomal degradation of PKM2 in HCC cells, even in Rac1 signaling-activated HCC cell lines. Here, ARHGAP24 is linked to hepatocellular carcinoma.