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, sorafenib 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 promotes cell proliferation and sorafenib resistance in HCC by inducing AKT-S473 phosphorylation. After palmitoylation 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 competitively inhibits PCSK9 palmitoylation, suppressing AKT phosphorylation and augmenting the antitumor effects of sorafenib in HCC.索拉非尼（Sorafenib）目前是晚期肝细胞癌（hepatocellular carcinoma, HCC）的一线治疗药物。然而，索拉非尼耐药仍是临床面临的重大挑战。AKT信号通路异常激活是驱动肝细胞癌患者产生索拉非尼耐药的关键机制。前蛋白转化酶枯草溶菌素/kexin9型（Proprotein convertase subtilisin/kexin type 9, PCSK9）在抗肿瘤免疫应答中发挥关键调控作用。本研究证实，异常高表达的PCSK9可通过诱导AKT蛋白S473位点磷酸化，促进肝细胞癌细胞增殖并介导索拉非尼耐药。PCSK9在半胱氨酸600位发生棕榈酰化修饰后，其与张力蛋白同源物（tensin homolog, PTEN）的结合亲和力显著升高，进而诱导溶酶体介导的PTEN降解，最终激活AKT信号通路。本研究鉴定出锌指DHHC型棕榈酰转移酶16（zinc finger DHHC-type palmitoyltransferase 16, ZDHHC16）为介导PCSK9半胱氨酸600位棕榈酰化的棕榈酰转移酶。本研究还开发了一种具有生物活性的PCSK9源性多肽，该多肽可竞争性抑制PCSK9的棕榈酰化修饰，进而抑制AKT磷酸化，增强索拉非尼在肝细胞癌中的抗肿瘤效应。