Miao Ting, Liu Ying, Qadiri Mujeeb, Asara John M, Hu Yanhui, Sun Xiaomei, Dibble Christian, Perrimon Norbert
Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.
Mass Spectrometry Core, Beth Israel Deaconess Medical Center and Department of Medicine, Harvard Medical School, Boston, MA USA.
bioRxiv. 2025 Aug 11:2025.08.08.669325. doi: 10.1101/2025.08.08.669325.
Coenzyme A (CoA), derived from Vitamin B5 (VB5), is essential for lipid metabolism, energy production, and cell proliferation. While the intracellular functions of CoA are well characterized, its tissue-specific regulation and systemic physiological roles remain poorly understood. Here, using , we uncover a gut-renal circuit in which dietary VB5 stimulates CoA biosynthesis specifically in the Malpighian tubules (MTs, the fly kidney), non-autonomously impacting gut homeostasis. We show that Myc boosts renal CoA production by directly upregulating ( homolog) and downregulating in the MTs. Elevated CoA biosynthesis enhances the mevalonate-isoprenoid pathway activity in the gut, promoting intestinal stem cell proliferation. We further demonstrate that renal CoA production is required for gut tumor growth in a fly model. Consistently, and genes within the CoA-isoprenoid axis display strong association with clinical outcomes in human cancers. Together, our findings establish that Myc-driven CoA metabolism generates an inter-organ signal that couples VB5 availability to stem cell control and tumor growth, and identify the CoA-isoprenoid axis as a targetable metabolic vulnerability in cancer.
辅酶A（CoA）源自维生素B5（VB5），对脂质代谢、能量产生和细胞增殖至关重要。虽然CoA的细胞内功能已得到充分表征，但其组织特异性调节和全身生理作用仍知之甚少。在这里，我们通过[具体实验手段]发现了一条肠道-肾脏回路，其中膳食VB5特异性地刺激果蝇马氏管（MTs，即果蝇的肾脏）中的CoA生物合成，非自主性地影响肠道稳态。我们表明，Myc通过直接上调MTs中的[基因名称]（[基因名称]的同源物）和下调[基因名称]来促进肾脏CoA的产生。CoA生物合成的增加增强了肠道中甲羟戊酸-类异戊二烯途径的活性，促进肠道干细胞增殖。我们进一步证明，在果蝇模型中，肠道肿瘤生长需要肾脏产生CoA。一致地，CoA-类异戊二烯轴内的[基因名称]和基因与人类癌症的临床结果显示出强烈关联。总之，我们的研究结果表明，Myc驱动的CoA代谢产生了一种器官间信号，将VB5的可用性与干细胞控制和肿瘤生长联系起来，并将CoA-类异戊二烯轴确定为癌症中一个可靶向的代谢弱点。
