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Small-molecule TFEB pathway agonists that ameliorate metabolic syndrome in mice and extend C. elegans lifespan

Chensu Wang, Hanspeter Niederstrasser, Peter M. Douglas, Rueyling Lin, Juan Jaramillo, Yang Li, Nathaniel W. Oswald, Anwu Zhou, Elizabeth A. McMillan, Saurabh Mendiratta, Zhaohui Wang, Tian Zhao, Zhiqaing Lin, Min Luo, Gang Huang

Nature Communications · 2017 · ▲ 154 citations

Mitochondrial dysfunction Caloric restriction C. elegans Human Mouse

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Abstract

Abstract Drugs that mirror the cellular effects of starvation mimics are considered promising therapeutics for common metabolic disorders, such as obesity, liver steatosis, and for ageing. Starvation, or caloric restriction, is known to activate the transcription factor EB (TFEB), a master regulator of lipid metabolism and lysosomal biogenesis and function. Here, we report a nanotechnology-enabled high-throughput screen to identify small-molecule agonists of TFEB and discover three novel compounds that promote autophagolysosomal activity. The three lead compounds include the clinically approved drug, digoxin; the marine-derived natural product, ikarugamycin; and the synthetic compound, alexidine dihydrochloride, which is known to act on a mitochondrial target. Mode of action studies reveal that these compounds activate TFEB via three distinct Ca 2+ -dependent mechanisms. Formulation of these compounds in liver-tropic biodegradable, biocompatible nanoparticles confers hepatoprotection against diet-induced steatosis in murine models and extends lifespan of Caenorhabditis elegans . These results support the therapeutic potential of small-molecule TFEB activators for the treatment of metabolic and age-related disorders.

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Provenance

Source: OpenAlex
DOI: 10.1038/s41467-017-02332-3
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Fetched: 2026-06-18 MST

Cite this

APA

Wang, C., Niederstrasser, H., Douglas, P.M., Lin, R., Jaramillo, J., Li, Y., Oswald, N.W., Zhou, A., McMillan, E.A., Mendiratta, S., Wang, Z., Zhao, T., Lin, Z., Luo, M., Huang, G., Brekken, R.A., Posner, B.A., MacMillan, J.B., Gao, J., & White, M.A. (2017). Small-molecule TFEB pathway agonists that ameliorate metabolic syndrome in mice and extend C. elegans lifespan. <em>Nature Communications</em>. https://doi.org/10.1038/s41467-017-02332-3

Vancouver

Wang C, Niederstrasser H, Douglas PM, Lin R, Jaramillo J, Li Y, et al. Small-molecule TFEB pathway agonists that ameliorate metabolic syndrome in mice and extend C. elegans lifespan. Nature Communications. 2017. doi:10.1038/s41467-017-02332-3.

BibTeX

@article{chensu2017Smallm, title = {Small-molecule TFEB pathway agonists that ameliorate metabolic syndrome in mice and extend C. elegans lifespan}, author = {Chensu Wang and Hanspeter Niederstrasser and Peter M. Douglas and Rueyling Lin and Juan Jaramillo and Yang Li and Nathaniel W. Oswald and Anwu Zhou and Elizabeth A. McMillan and Saurabh Mendiratta and Zhaohui Wang and Tian Zhao and Zhiqaing Lin and Min Luo and Gang Huang and Rolf A. Brekken and Bruce A. Posner and John B. MacMillan and Jinming Gao and Michael A. White}, journal = {Nature Communications}, year = {2017}, doi = {10.1038/s41467-017-02332-3}, }