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Cited by 13Lysosomal Storage Disorders ResearchGlycogen Storage Diseases and MyoclonusBiomedical Research and Pathophysiology

Small-molecule activation of TFEB alleviates Niemann–Pick disease type C via promoting lysosomal exocytosis and biogenesis

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Du, Kaili, Chen, Hongyu, Pan, Zhaonan, Zhao, Mengli, Cheng, Shixue, Luo, Yu, Zhang, Wenhe, Li, Dan·2025·eLife
DOI 10.7554/elife.103137PMC PMC11970905

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Abstract

Niemann–Pick disease type C (NPC) is a devastating lysosomal storage disease characterized by abnormal cholesterol accumulation in lysosomes. Currently, there is no treatment for NPC. Transcription factor EB (TFEB), a member of the microphthalmia transcription factors (MiTF), has emerged as a master regulator of lysosomal function and promoted the clearance of substrates stored in cells. However, it is not known whether TFEB plays a role in cholesterol clearance in NPC disease. Here, we show that transgenic overexpression of TFEB, but not TFE3 (another member of MiTF family) facilitates cholesterol clearance in various NPC1 cell models. Pharmacological activation of TFEB by sulforaphane (SFN), a previously identified natural small-molecule TFEB agonist by us, can dramatically ameliorate cholesterol accumulation in human and mouse NPC1 cell models. In NPC1 cells, SFN induces TFEB nuclear translocation via a ROS-Ca 2+ -calcineurin-dependent but MTOR-independent pathway and upregulates the expression of TFEB-downstream genes, promoting lysosomal exocytosis and biogenesis. While genetic inhibition of TFEB abolishes the cholesterol clearance and exocytosis effect by SFN. In the NPC1 mouse model, SFN dephosphorylates/activates TFEB in the brain and exhibits potent efficacy of rescuing the loss of Purkinje cells and body weight. Hence, pharmacological upregulating lysosome machinery via targeting TFEB represents a promising approach to treat NPC and related lysosomal storage diseases, and provides the possibility of TFEB agonists, that is, SFN as potential NPC therapeutic candidates.

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  • Impairment of mitophagy has been implicated in disease through strong genetic links with PD, specifically the genes LRRK2, PARKIN, and PINK1.

    “Impairment of mitophagy has been implicated in disease through strong genetic links with PD, specifically the genes LRRK2, PARKIN, and PINK1.51–55”

    From The lysosome and proteostatic stress at the intersection of pediatric neurological disorders and adult neurodegenerative diseases (2025) · cites this paper as [51]

    The Introduction (page unavailable) discusses TFEB, autophagy, and Parkinson’s disease, while the References list a study of mitophagy downstream of Parkin. Neither passage states that impaired mitophagy is genetically linked to Parkinson’s disease through LRRK2, PARKIN, and PINK1. Searches for those genes and the claimed genetic link found no supporting passage in our copy. (LLM, conf=0.72)

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Cited by

Sorted by citations

Authors
Du, K., Chen, H., Pan, Z., Zhao, M., Cheng, S., Luo, Y., Zhang, W., & Li, D.
Affiliations
  • University of Michigan (US)
  • Zhejiang University of Technology (CN)
Corresponding author
Li, Dan
ORCID
Venue
eLife
Publisher
eLife Sciences Publications, Ltd
Published
2025-04-04
Volume
13
ISSN
2050-084X (ISSN-L)
DOI
10.7554/elife.103137
PMC
PMC11970905
OpenAlex
W4404961139
Cited by
13
References
3
Citations by year
2026: 7 · 2025: 6
Type
posted content
Language
en
Open access
Licence
Locations
  • eLife (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Natural Science Foundation of China (31600823)
  • Calygene Biotechnology Inc (XT [2016]008@)
  • Lysoway Therapeutics, Inc (KYY-HX-20210129)
Topics
  • Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
  • Health Sciences › Medicine › Rheumatology › Glycogen Storage Diseases and Myoclonus
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Biomedical Research and Pathophysiology
Keywords
Niemann-Pick disease type C, TFEB, sulforaphane, lysosomal exocytosis, lysosomal biogenesis, cholesterol clearance, lysosomal storage disease, calcineurin, TFEB nuclear translocation, Purkinje cells, small molecule agonists, TFE3
MeSH terms
Animals, Cell Line, Cholesterol, Exocytosis, Humans, Lysosomes, Isothiocyanates, Mice, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, Niemann-Pick Disease, Type C

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