KLHL7 promotes hepatocellular carcinoma progression and molecular therapy resistance by degrading RASA2

Hepatocellular carcinoma (HCC) is a common aggressive tumor with a poor prog-nosis, and patients often seem to be refractory to the use of therapeutic drugs. In this study, we found that the KLHL7 expression was upregulated in HCC that was associated with poor patient prognosis. KLHL7 has been found to promote HCC development in both in vitro and in vivo experiments. Mechanistically, RASA2, a RAS GAP, was identified as a substrate of KLHL7. Upregulation of KLHL7 by growth factors promotes K48-linked polyubiquitination of RASA2 for degrada-tion via the proteasomal pathway. Our in vivo experiments revealed that inhibi-tion of KLHL7 in combination with lenvatinib treatment resulted in efficient killing of HCC cells. Together, these findings demonstrate a role for KLHL7 in HCC and reveal a mechanism by which growth factors regulate the RAS-MAPK pathway. It represents a potential therapeutic target for HCC.