S-palmitoylation of PCSK9 induces sorafenib resistance in liver cancer by activating the PI3K/AKT pathway

Sorafenib is currently the first-line treatment for advanced hepatocellular carcinoma (HCC). However, sora-fenib resistance remains a significant challenge. Aberrant AKT signaling activation is a crucial mechanism driving sorafenib resistance in HCC. Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a vital role in antitumor immune responses. In this study, we demonstrate that aberrant PCSK9 upregulation pro-motes cell proliferation and sorafenib resistance in HCC by inducing AKT-S473 phosphorylation. After palmi-toylation at cysteine 600, the binding affinity between PCSK9 and tensin homolog (PTEN) is dramatically increased, inducing lysosome-mediated PTEN degradation and subsequent AKT activation. We identify zinc finger DHHC-type palmitoyltransferase 16 (ZDHHC16) as a palmitoyltransferase that promotes PCSK9 palmitoylation at cysteine 600. We also develop a biologically active PCSK9-derived peptide that competi-tively inhibits PCSK9 palmitoylation, suppressing AKT phosphorylation and augmenting the antitumor effects of sorafenib in HCC.

Automated summary

This study demonstrates that aberrant PCSK9 upregulation promotes cell proliferation and sorafenib resistance in HCC by inducing AKT activation. Additionally, competitive inhibition of PCSK9 palmitoylation enhances the antitumor effects of sorafenib in HCC.