ZDHHC9通过介导ACSL3的棕榈酰化作用，调节脂质代谢重编程，进而促进结直肠癌对西妥昔单抗的耐药性。

Abstract

ZDHHC9 is highly expressed in colorectal cancer (CRC) tissues and correlates with poor prognosis, promoting Cetuximab resistance • The palmitoylation inhibitor 2-BP enhances CRC sensitivity to Cetuximab, implicating palmitoylation in drug resistance • ZDHHC9 interacts with ACSL3 and increases its palmitoylation at the C468 site, driving malignant progression • ACSL3 overexpression reverses the inhibitory effects of ZDHHC9 knockdown, confirming the functional axis • ZDHHC9 is identified as a potential therapeutic target to overcome drug resistance in CRC Tumor metastasis and drug resistance are the leading causes of mortality in patients with colorectal cancer (CRC). Protein palmitoylation exerts a pivotal role in the metabolic reprogramming across various malignancies. However, the precise mechanisms underlying its contribution to CRC metastasis and drug resistance via lipid metabolism reprogramming remain elusive. Therefore, this study aimed to elucidate the specific role of ZDHHC9 in conferring Cetuximab resistance in CRC. Initial phenotypic screening with the broad-spectrum inhibitor 2-BP implicated palmitoylation in Cetuximab resistance. Subsequently, targeted genetic experiments identified ZDHHC9 as the specific molecular driver. Furthermore, ZDHHC9 was significantly upregulated in CRC tissues and strongly correlated with poor patient prognosis. Subsequent in vitro and in vivo experiments demonstrated that ZDHHC9 functionally promoted Cetuximab resistance in CRC. Mechanistically, ZDHHC9 physically interacted with ACSL3 and enhanced its palmitoylation, thereby driving the malignant progression of CRC. Moreover, we identified cysteine 468 (C468) as the critical residue responsible for the palmitoylation of ACSL3. Notably, ectopic overexpression of ACSL3 effectively rescued the suppression of CRC cell proliferation induced by ZDHHC9 depletion. In conclusion, our findings establish the ZDHHC9-ACSL3 axis as a preclinically validated resistance driver and an acti