Targeting polyunsaturated fatty acids desaturase FADS1 inhibits renal cancer growth via ATF3-mediated ER stress response

作者：Gioia Heravi, Zhenjie Liu, Mackenzie K. Herroon, Alexis Wilson, Yang-Yi Fan, Yang Jiang, Nivisa Vakeesan, Tao Li, Zheyun Peng, Kezhong Zhang, Jing Li, Robert S. Chapkin, Izabela Podgorski, Wanqing Liu · 发表于：Biomedicine & Pharmacotherapy · 年份：2025 · DOI：10.1016/j.biopha.2025.118006 · 被引用次数：9 · 研究领域：Cancer, Lipids, and Metabolism、Endoplasmic Reticulum Stress and Disease、Cancer, Hypoxia, and Metabolism

Fatty Acid Desaturase 1 (FADS1) is a rate-limiting enzyme controlling the bioproduction of long-chain polyunsaturated fatty acids (PUFAs). Increasing studies suggest that FADS1 is a potential cancer target. Our previous research has demonstrated the significant role of FADS1 in cancer biology and patient survival, especially in kidney cancers. We aim to explore the underlying mechanism in this study. We found that pharmacological inhibition or knockdown of the expression of FADS1 significantly reduced the intracellular conversion of long-chain PUFAs, effectively inhibits renal cancer cell proliferation, and induces cell cycle arrest. The stable knockdown of FADS1 also significantly inhibits tumor formation in vivo . Mechanistically, we showed that while FADS1 inhibition induces endoplasmic reticulum (ER) stress, FADS1 expression is augmented by ER-stress inducer, suggesting a necessary role of PUFA production in response to ER stress. FADS1-inhibition sensitized cellular response to ER stress inducers, leading to cell apoptosis. Also, FADS1 inhibition-induced ER stress leads to activation of the PERK/eIF2α/ATF4/ATF3 pathway. Inhibiting PERK or knockdown of ATF3 rescued FADS1 inhibition-induced ER stress and cell growth suppression, while ATF3-overexpression aggravates the FADS1 inhibition-induced cell growth suppression and leads to cell death. Metabolomic analysis revealed that FADS1 inhibition results in decreased level of UPD-N-Acetylglucosamine, a critical mediator of the...