Cullin 3/Kelch-like protein 18 promote ferroptosis and inhibit hepatocellular carcinoma progression through ubiquitination and degradation of glutathione peroxidase 4.

Hepatocellular carcinoma (HCC) is one of the major global health challenge. As a newly discovered molecular mechanism, ferroptosis offers great potential to eliminate cancer cells. This study identified KLHL18 (Kelch-like Protein 18), an understudied adaptor of the Cullin3 E3 ubiquitin ligase complex, as a tumor suppressor in HCC. We demonstrated that KLHL18 was downregulated in HCC tissues and that its overexpression suppressed tumor growth both in vitro and in vivo. Mechanistically, KLHL18 promotes ferroptosis by interacting with GPX4, a key glutathione peroxidase that prevents lipid peroxidation, and promoting GPX4 ubiquitination, leading to proteasomal degradation. This proteasomal degradation is associated with K48-linked ubiquitination, with lysine 191 of GPX4 identified as a major ubiquitination site. Furthermore, KLHL18 expression modulated ferroptotic and antitumor responses of HCC cells to sorafenib. Our findings reveal a novel regulatory axis in which KLHL18-mediated GPX4 degradation contributes to ferroptotic cell death and suppresses HCC progression, suggesting that KLHL18 is a potential biomarker and molecular target warranting further clinical investigation.