Hijacking Cellular S-Acylation with Molecular Assemblies Rewires Oncogenic Signaling

Authors

Liu, Z., Tan, W., Zhang, Q., Zou, L., Xu, B.

Abstract

KRAS-mutant cancers are generally treated by suppressing oncogenic signaling. Here, we investigated whether endogenous lipidation machinery could instead be used to spatially perturb that signaling. The thioester-bearing peptide precursor Stb-DPhe-DPhe-SAc (1) potently reduced PANC-1 cell viability and formed a palmitoylated product in treated cells. Synthetic palmitoylated 1 displayed increased assembly propensity, while fluorescent analogue 2 accumulated at the Golgi in a 2-bromopalmitate-sensitive manner. Compound 1 increased plasma-membrane-associated KRAS staining and ERK/AKT phosphorylation and induced pronounced LC3B and p62 remodeling. Inhibition of palmitoylation suppressed Golgi accumulation, attenuated the LC3B response, and rescued cell viability. These findings support a model in which cellular S-acylation drives organelle-localized molecular assembly that perturbs KRAS localization, oncogenic signaling, and associated stress responses. This work identifies endogenous lipidation machinery as a synthetic handle for spatial control of cancer signaling.

Preprint server: bioRxiv
The authors list and abstract were imported from bioRxiv on 06 Nov 2026.

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