Mitochondrial ACSS1 Links Acetate Metabolism to Pyrimidine Biosynthesis in Nutrient-Stressed B-Cell Lymphomas

Abstract

Acetate serves as an alternative carbon source in nutrient-limited tumors, yet its role in supporting nucleotide biosynthesis remains poorly understood. Here, we identify the mitochondrial enzyme ACSS1 as a key metabolic driver in mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), and chronic lymphocytic leukemia (CLL). ACSS1 is frequently overexpressed and catalyzes the conversion of acetate to mitochondrial acetyl-CoA, sustaining oxidative metabolism and biosynthesis under nutrient stress. Genetic silencing of ACSS1 impairs mitochondrial respiration and disrupts acetate incorporation into acetyl-CoA, TCA cycle intermediates, glutamate, and aspartate, while markedly reducing 13C-acetate labeling of dihydroorotate and orotate, intermediates in de novo pyrimidine synthesis. Untargeted metabolomics reveal enrichment of pyrimidine biosynthesis pathways in ACSS1-high cells. Notably, acetate or uridine supplementation rescues the growth of ACSS1-deficient cells, confirming a functional link between acetate metabolism and nucleotide synthesis. Importantly, in vivo studies using luciferase-labeled JeKo-1 and Maver mantle cell lymphoma xenografts demonstrate that ACSS1 knockdown significantly suppresses tumor growth. NSG mice injected with ACSS1-silenced cells exhibit a marked reduction in tumor burden, as measured by bioluminescence imaging and total photon flux, with significant differences observed at days 14 and 21 post-injection. These findings establish that ACSS1 is required not only for metabolic adaptation in vitro but also for lymphoma progression in vivo. Collectively, our results uncover an ACSS1-dependent mitochondrial acetate-pyrimidine axis that sustains lymphoma growth and represents a previously unrecognized therapeutic vulnerability. Statement of SignificanceThis study identifies ACSS1 as a critical metabolic vulnerability in mantle cell lymphoma (MCL), linking mitochondrial acetate metabolism to de novo pyrimidine biosynthesis and tumor progression. We demonstrate that ACSS1 is frequently overexpressed in MCL and is essential for converting acetate into mitochondrial acetyl-CoA, thereby sustaining TCA cycle activity, nucleotide production, and cell survival under nutrient stress. Loss of ACSS1 disrupts this acetate-pyrimidine axis, impairing oxidative metabolism and reducing lymphoma cell viability in vitro. Importantly, ACSS1 silencing significantly suppresses tumor growth in vivo, establishing its requirement for lymphoma progression. The ability of acetate or uridine supplementation to rescue ACSS1-deficient cells further highlights the functional coupling between mitochondrial acetate utilization and nucleotide synthesis. Together, these findings reveal a previously unrecognized mechanism of metabolic adaptation in aggressive lymphomas and offer ACSS1-mediated acetate metabolism as a promising therapeutic target.