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ResearchIn-Press PreviewMetabolismNeuroscience Open Access | 10.1172/jci.insight.201466

Metabolic reprogramming is critical to microglial activation in Huntington’s disease

Abhishek Jauhari,1 Adam C. Monek,1 Olena S. Abakumova,1 Tanisha Singh,1 Sukhman Singh,1 Xiaomin Wang,1 Carley S. Clise,1 Diane L. Carlisle,1 and Robert M. Friedlander2

1Neuroapoptosis Laboratory, Department of Neurological Surgery, University of Pittsburgh, School of Medicine, Pittsburgh, United States of America

2Helexva Inc., Pittsburgh, United States of America

Find articles by Jauhari, A. in: PubMed | Google Scholar |

1Neuroapoptosis Laboratory, Department of Neurological Surgery, University of Pittsburgh, School of Medicine, Pittsburgh, United States of America

2Helexva Inc., Pittsburgh, United States of America

Find articles by Monek, A. in: PubMed | Google Scholar

1Neuroapoptosis Laboratory, Department of Neurological Surgery, University of Pittsburgh, School of Medicine, Pittsburgh, United States of America

2Helexva Inc., Pittsburgh, United States of America

Find articles by Abakumova, O. in: PubMed | Google Scholar

1Neuroapoptosis Laboratory, Department of Neurological Surgery, University of Pittsburgh, School of Medicine, Pittsburgh, United States of America

2Helexva Inc., Pittsburgh, United States of America

Find articles by Singh, T. in: PubMed | Google Scholar

1Neuroapoptosis Laboratory, Department of Neurological Surgery, University of Pittsburgh, School of Medicine, Pittsburgh, United States of America

2Helexva Inc., Pittsburgh, United States of America

Find articles by Singh, S. in: PubMed | Google Scholar

1Neuroapoptosis Laboratory, Department of Neurological Surgery, University of Pittsburgh, School of Medicine, Pittsburgh, United States of America

2Helexva Inc., Pittsburgh, United States of America

Find articles by Wang, X. in: PubMed | Google Scholar

1Neuroapoptosis Laboratory, Department of Neurological Surgery, University of Pittsburgh, School of Medicine, Pittsburgh, United States of America

2Helexva Inc., Pittsburgh, United States of America

Find articles by Clise, C. in: PubMed | Google Scholar

1Neuroapoptosis Laboratory, Department of Neurological Surgery, University of Pittsburgh, School of Medicine, Pittsburgh, United States of America

2Helexva Inc., Pittsburgh, United States of America

Find articles by Carlisle, D. in: PubMed | Google Scholar |

1Neuroapoptosis Laboratory, Department of Neurological Surgery, University of Pittsburgh, School of Medicine, Pittsburgh, United States of America

2Helexva Inc., Pittsburgh, United States of America

Find articles by Friedlander, R. in: PubMed | Google Scholar

Published April 2, 2026 - More info

JCI Insight. https://doi.org/10.1172/jci.insight.201466.
Copyright © 2026, Jauhari et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published April 2, 2026 - Version history
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Abstract

Huntington’s disease (HD) is a fatal neurodegenerative disease caused by an expanded polyglutamine (CAG) repeat in the N-terminal of the Huntingtin protein (HTT). Microglial activation and elevated pro-inflammatory cytokines are observed in HD brains, but the mechanisms regulating neuroinflammation and microglial activation are poorly understood. Metformin-mediated neuroprotection has been demonstrated in experimental models of neurodegeneration, including HD. We found that metformin inhibits mitochondrial DNA (mtDNA) release and subsequent neuroinflammation in the cortex and striatum of a mouse model of HD. Moreover, elevated pro-inflammatory cytokines and microglial activation are inhibited by metformin in HD transgenic mice brain. Metformin reduced pathological microglial clusters and shifted towards a quiescent, homeostatic phenotype. Metformin improved aberrant immunometabolism in HD mouse brain and primary microglia. Mechanistically found that metformin regulates mitochondrial fission, reprograms deregulated metabolism in HD microglia, and controls microglial activation and inflammation in HD transgenic mice.

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