Abstract
Neuroinflammation is a major pathogenic mechanism underlying neurodegenerative diseases. Understanding how neuroinflammation is regulated is critical to therapeutic development. Here, we report that dynaminrelated protein 1 (DRP1), well-recognized for its role in mitochondrial fission, also functions as a transcription factor that regulates neuroinflammation. Using multiple inflammatory models, we demonstrate that upon stimulation with pro-inflammatory lipopolysaccharides (LPS), DRP1 translocates from the cytosol to the nucleus, where it binds to the promoter region of Rela (encoding NF-κB p65) to activate its gene products and other downstream inflammatory cytokines. Our data further reveal a significant role of the proinflammatory lipocalin-2 in the brain. In combination, this study identifies a previously unrecognized function of DRP1 in mediating neuroinflammation via the NF-κB-lipocalin-2 axis and highlights DRP1-mediated pathways as potential therapeutic targets for neurodegenerative and other inflammation-related diseases.
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Acknowledgements
This study was supported in part by the National Institute of Environmental Health Sciences (NIEHS) of the National Institutes of Health (NIH) under Award Number R35ES030523 (to KT). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
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K.T., Y.L., and R.F. contributed to the study conception and design. Experiments and data analysis were performed by Y.L., R.F., H.B., S.S., and E.T. Y.L. and K.T. were involved in drafting and revision of the manuscript. All the other authors commented on previous versions of the manuscript and approved of the final version.
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Lai, Y., Fan, R.Z., Brown, H.J. et al. DRP1 induces neuroinflammation via transcriptional regulation of NF-ĸB.. Nat Commun (2026). https://doi.org/10.1038/s41467-026-70780-x
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DOI: https://doi.org/10.1038/s41467-026-70780-x
