Biology subjects

Hirschey, M.

Publications and source records attributed to Hirschey, M..

3 recordsLinked to original sources

bioRxiv2026

datadrivenhypothesis.org: A resource for metabolic gene discovery through integrated pathway co-essentiality mapping

datadrivenhypothesis.org (DDH) integrates gene dependency, expression, literature data, and beyond from [~]20,000 human genes to reveal hidden metabolic connections. Through pathway-level co-essentiality analysis with novelty scoring, DDH uncovered unexpected links including Complex II coupled to purine nucleotide biosynthesis. This broad platform offers intuitive tools for hypothesis generation via gene queries, pathway analysis, and network visualization, plus publication-ready downloads. Automated updates make DDH a dynamic resource, bridging genes with unknown function to actionable metabolic insights.

systems biology↗

bioRxiv2025

SIRT4 Controls Macrophage Function and Wound Healing through Control of Protein Itaconylation in Mice

Proper regulation of inflammatory responses is essential for organismal health. Dysregulation can lead to accelerated development of the diseases of aging and the aging process itself. Here, we identify a novel enzymatic activity of the mitochondrial sirtuin SIRT4 as a lysine deitaconylase that regulates macrophage inflammatory responses. Itaconate is a metabolite abundantly produced in activated macrophages. We find it forms a protein modification called lysine itaconylation. Using biochemical and proteomics approaches, we demonstrate that SIRT4 efficiently removes this modification from target proteins both in vitro and in vivo. In macrophages, elevated protein itaconylation increases upon LPS stimulation, coinciding with elevated SIRT4 expression. SIRT4-deficient macrophages exhibit significantly increased IL-1{beta} production in response to LPS stimulation. This phenotype is intrinsic to macrophages, as demonstrated by both lentiviral over-expression and acute SIRT4 knockdown models. Mechanistically, we identify key enzymes in branched-chain amino acid (BCAA) metabolism as targets of hyperitaconylation in SIRT4-deficient macrophages. The BCKDH complex component dihydrolipoamide branched chain transacylase E2 (DBT) is hyperitaconylated and has reduced BCKDH activity in SIRT4KO macrophages. Physiologically, SIRT4-deficient mice exhibit significantly delayed wound healing, demonstrating a consequence of dysregulated macrophage function. Our data reveal a novel protein modification pathway in immune cells and establish SIRT4 as a critical regulator at the intersection of metabolism and inflammation. These findings have implications for understanding immune dysregulation in aging and metabolic disease.

molecular biology↗

bioRxiv2020

In vivo optical metabolic imaging of long-chain fatty acid uptake in orthotopic models of triple negative breast cancer

Targeting a tumors metabolic dependencies is a clinically actionable therapeutic approach, but identifying subtypes of tumors likely to respond remains difficult. The use of lipids as a nutrient source is of particular importance, especially in breast cancer. Imaging techniques offer the opportunity to quantify nutrient use in preclinical models to aid in the development of new drugs to restrict uptake or utilization of these nutrients. We describe a fast and dynamic approach to image fatty acid uptake in vivo, a tool relevant to study tumor metabolic reprogramming or for studying the effectiveness of drugs targeting lipid metabolism spanning beyond breast cancer and optical imaging alone. Specifically, we developed a quantitative optical approach to spatially and longitudinally map the kinetics of long-chain fatty acid uptake in in vivo murine models of breast cancer using a fluorescently labeled palmitate molecule, Bodipy FL c16. We chose intra-vital microscopy of mammary tumor windows to validate our approach in two orthotopic breast cancer models: a MYC-overexpressing transgenic triple-negative breast cancer (TNBC) model and a murine model of the 4T1 family. Following injection, Bodipy FL c16 fluorescence increased and reached its maximum after approximately 30 minutes, with the signal remaining stable during the 30-80-minute post-injection period. We used the fluorescence at 60 minutes (Bodipy60), the mid-point in the plateau region, as a summary parameter to quantify Bodipy FL c16 fluorescence in subsequent experiments. Using our imaging platform, we observed a two- to four-fold decrease in fatty acid uptake in response to the downregulation of the MYC oncogene consistent with findings from in vitro metabolic assays. In contrast, our imaging studies report an increase in fatty acid uptake with tumor aggressiveness (6NR, 4T07, and 4T1), and uptake was significantly decreased after treatment with a fatty acid transport inhibitor, perphenazine, in both normal mammary pads and in the most aggressive 4T1 tumor model. Our approach fills an important gap between in vitro assays, which provide rich metabolic information but at static time points, and imaging approaches that can visualize metabolism in whole organs, but which suffer from poor resolution.

bioengineering↗