A research team led by Associate Professor Peng Jiang at the School of Life Sciences, Tsinghua University, has discovered how metabolic reprogramming in macrophages enhances antiviral innate immune responses. Their study, titled "Metabolic remodelling produces fumarate via the aspartate–argininosuccinate shunt in macrophages as an antiviral defence" was published in Nature Microbiology on April 18, 2025. And this work has also been highlighted by the journal, with commentary by Prof. Luke A.J. O'Neill and Yukun Min.
The innate immune system, particularly macrophages, relies heavily on metabolic remodeling to respond to environmental stress and pathogen invasion. While previous research has indicated that metabolic changes can affect macrophage function, how macrophages selectively rewire specific metabolic pathways during viral infection remains poorly understood.
Previously, the Jiang laboratory has discovered that dysregulated urea cycle metabolism governs the fate of both tumor cells and macrophages (Nature, 2019; Molecular Cell, 2022), and has systematically investigated the role of TCA cycle intermediates in anti-tumor immunity and immune regulation (Cell Metabolism, 2023; Nature Chemical Biology, 2022).
This study demonstrates that early during viral infection, macrophages undergo a coordinated rewiring of the urea cycle and the tricarboxylic acid (TCA) cycle, forming a closed-loop metabolic bypass termed the aspartate–argininosuccinate (AAS) shunt. Through RNA sequencing, untargeted metabolomics, and isotope tracing, the researchers identified that cytosolic argininosuccinate synthase 1 (ASS1) drives this shunt to produce fumarate, which in turn promotes inflammatory signaling.
Functionally, loss of ASS1 significantly reduced intracellular fumarate levels, dampened interferon-β (IFN-β) production, and impaired mitochondrial respiration. Strikingly, either viral infection or exogenous supplementation with fumarate esters enhanced IFN-β expression by promoting succination of MAVS (mitochondrial antiviral-signaling protein), thereby activating the RIG-I-like receptor signaling pathway. This mechanism was validated in infections with vesicular stomatitis virus (VSV), Sendai virus, and influenza A virus. Notably, monocytes from Ebola virus-infected patients also showed elevated ASS1 expression, and ASS1-deficient macrophages in mice exhibited impaired interferon responses following VSV infection.
This work highlights the ASS1-driven AAS shunt as a critical source of fumarate in antiviral defence and uncovers a novel mechanism by which metabolic rewiring enhances innate immune responses. These findings provide a promising metabolic target for immunomodulation during viral infection.
The study was conducted by Dr. Wenjun Xia (postdoctoral fellow), Dr. Youxiang Mao (postdoctoral fellow), and Ziyan Xia (PhD candidate, Class of 2023), who contributed equally to the work. Associate Professor Peng Jiang served as the corresponding author. The research was also supported by Drs. Gong Cheng, Haifeng Wang and Conggang Zhang at Tsinghua University and Dr. Fuping You at Peking University.
Figure 1. Viral infection-induced metabolic reprogramming promotes fumarate production to enhance antiviral innate immune responses.
Original article:
Editor: Li Han
