ACACA depletion activates the cPLA2–arachidonic acid–NF-κB axis to drive inflammatory reprogramming in androgen receptor-independent prostate cancer

作者：Shaoyou Liu, Yupeng Chen, Jian Chen, Jinchuang Li, Zhenguo Liang, Xinyue Mei, Yuanfa Feng, Zhaodong Han, Funeng Jiang, Yongding Wu, Huijing Tan, Hongwei Luo, Huichan He, Jiarun Lai, Weide Zhong · 发表于：Cell Communication and Signaling · 年份：2025 · DOI：10.1186/s12964-025-02363-0 · 被引用次数：2 · 研究领域：Cancer, Lipids, and Metabolism、Prostate Cancer Treatment and Research、Inflammatory mediators and NSAID effects

BACKGROUND: Acetyl-CoA carboxylase alpha (ACACA) is a key enzyme in fatty acid biosynthesis and a proposed therapeutic target in prostate cancer. However, its role in androgen receptor-independent prostate cancer (ARIPC), an aggressive and treatment-resistant subtype, remains unclear. This study aimed to investigate the effects of ACACA depletion on ARIPC, with a focus on inflammation and metastasis. METHODS: ACACA expression patterns were analyzed across multiple metastatic castration-resistant prostate cancer (mCRPC) datasets. In ARIPC cell lines, ACACA was inhibited via both shRNA and the pharmacological inhibitor TOFA. Transcriptomic, metabolomic, and single-cell RNA sequencing data were used to identify downstream changes. Inflammatory signaling was assessed by qPCR, western blotting, and immunofluorescence. Cell migration was evaluated via wound healing and transwell assays, and the metastatic potential was examined in a mouse tail vein injection model. The roles of arachidonic acid (AA), cytosolic phospholipase A2 (cPLA2), and NF-κB signaling were further tested through targeted inhibition. RESULTS: ACACA expression was reduced in ARIPC and was negatively correlated with inflammatory pathways. Its inhibition upregulated proinflammatory cytokines and chemokines, elevated AA and eicosanoid levels, and increased cPLA2 expression. Single-cell RNA sequencing confirmed NF-κB signaling enrichment in ACACA-low tumor cells. Mechanistically, elevated AA activated NF-κB signaling...