Metabolic pathways, such as fatty acid oxidation and oxidative phosphorylation, can modulate inflammatory cells. However, little is known about the effects of the fatty acid synthesis pathway in macrophages on inflammation and cardiac remodeling after myocardial infarction (MI). Using spatial metabolomics, here we show that cardiac macrophages residing in the infarct synthesize de novo fatty acids and increase the production of fatty acid enzymes including ACLY and FASN. Mice deficient in myeloid Acly and Fasn have improved cardiac function after MI and reduced fibrosis. Combining Cleavage Under Targets and Release Using Nuclease (CUT&RUN), RNA sequencing analysis of Acly −/− macrophages, and macrophage-specific in vivo gene silencing, we demonstrate that ACLY acetylates the promoter region of the upstream regulator Krt17 , which drives the production of pro-fibrotic cytokines, including IL-33. Single-cell RNA sequencing of cardiac fibroblasts shows that the expansion of a population of fibroblasts (Fibroblast 5) expressing high levels of extracellular matrix genes after MI is confined in the absence of macrophage Acly . Finally, the analysis of spatial multi-omics data of human hearts with MI uncovers myofibroblasts with the Fibroblast 5 gene signature. These myofibroblasts are located near cardiac macrophages expressing high levels of ACLY. In summary, we show that macrophage ACLY and FASN are deleterious in MI pathogenesis.

Rapid hematopoietic adaptations are important for building and sustaining the biological response to β-glucan. The signals involved in these early events have not yet been fully explored. Given that type I interferons are produced in response to β-glucan and can profoundly impact hematopoietic stem cell (HSC) function, we hypothesized that this pathway may be involved in the early bone marrow response to β-glucan. In vivo administration of β-glucan led to local interferon-α production in the peritoneal cavity and bone marrow, upregulation of its receptor, IFNAR1, specifically on long-term hematopoietic stem cells (LT-HSCs), and broad expansion of downstream progenitor subpopulations. We demonstrate that intact type I interferon signaling is critical for β-glucan-mediated LT-HSC proliferation, mitochondrial activity, and glycolytic commitment. By determining that type I interferon signaling is important for LT-HSCs, which sit at the apex of the hematopoietic hierarchy, we uncover an important component of the early inflammatory response to β-glucan.
© 2025 The Author(s).

The tumor microenvironment (TME) is a unique metabolic niche that can inhibit T cell metabolism and cytotoxicity. To dissect the metabolic interplay between tumors and T cells, we establish an in vitro system that recapitulates the metabolic niche of the TME and allows us to define cell-specific metabolism. We identify tumor-derived lactate as an inhibitor of CD8+ T cell cytotoxicity, revealing an unexpected metabolic shunt in the TCA cycle. Metabolically fit cytotoxic T cells shunt succinate out of the TCA cycle to promote autocrine signaling via the succinate receptor (SUCNR1). Cytotoxic T cells are reliant on pyruvate carboxylase (PC) to replenish TCA cycle intermediates. By contrast, lactate reduces PC-mediated anaplerosis. The inhibition of pyruvate dehydrogenase (PDH) is sufficient to restore PC activity, succinate secretion, and the activation of SUCNR1. These studies identify PDH as a potential drug target to allow CD8+ T cells to retain cytotoxicity and overcome a lactate-enriched TME.
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