Lipid nanoparticle-mediated transcription factor EB mRNA delivery for the treatment of metabolic dysfunction-associated steatotic liver disease.
13 affiliations
- 1State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Key Laboratory of Innovative Cardiovascular Devices, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100037, China.
- 2Yunnan Key Laboratory of Innovative Diagnosis and Treatment of Circulatory Diseases, Fuwai Yunnan Hospital, Chinese Academy of Medical Sciences, Affiliated Cardiovascular Hospital of Kunming Medical University, Kunming, China.
- 3Department of Pharmacology, Joint Laboratory of Guangdong-Hong Kong Universities for Vascular Homeostasis and Diseases, School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong, 518055, China. [email protected].
- 4SUSTech Homeostatic Medicine Institute, School of Medicine, Southern University of Science and Technology, Shenzhen, 518055, China. [email protected].
- 5Department of Cardiology, The Eighth Affiliated Hospital, Zhongshan School of Medicine, Sun Yat-Sen University, Shenzhen, Guangdong, 518033, China.
- 6Department of Pharmacology, Joint Laboratory of Guangdong-Hong Kong Universities for Vascular Homeostasis and Diseases, School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong, 518055, China.
- 7SUSTech Homeostatic Medicine Institute, School of Medicine, Southern University of Science and Technology, Shenzhen, 518055, China.
- 8Department of Pharmacology, School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong, 518055, China.
- 9Key Laboratory of Tropical Translational Medicine of Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medicine and Life Sciences, Hainan Medical University, Haikou, China.
- 10SUSTech Homeostatic Medicine Institute, School of Medicine, Southern University of Science and Technology, Shenzhen, 518055, China. [email protected].
- 11Department of Pharmacology, School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong, 518055, China. [email protected].
- 12Department of Pharmacology, Joint Laboratory of Guangdong-Hong Kong Universities for Vascular Homeostasis and Diseases, School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong, 518055, China. [email protected].
- 13SUSTech Homeostatic Medicine Institute, School of Medicine, Southern University of Science and Technology, Shenzhen, 518055, China. [email protected].
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent disorder characterized by excessive hepatic lipid accumulation, frequently progressing to steatohepatitis, fibrosis, and cirrhosis. Transcription factor EB (TFEB) coordinates lysosomal biogenesis, autophagy, and lipid catabolism, and therefore represents a potential therapeutic target; however, safe and direct strategies for selectively enhancing hepatic TFEB activity remain limited. Here, liver-targeted lipid nanoparticles (LNPs) were developed to deliver mRNAs encoding wild-type TFEB or the constitutively active TFEB S211A mutant, and their efficacy was evaluated in cellular and choline-deficient, L-amino acid-defined high-fat diet (CDAHFD)-induced mouse models of MASLD. LNP-mediated delivery increased hepatic TFEB expression, enhanced autophagic flux, and reprogrammed metabolic pathways toward fatty acid oxidation (e.g., CPT1A and ACOX1) while suppressing the expression of lipogenic genes (e.g., FASN, ACC, and SREBP1). Consequently, targeted TFEB mRNA therapy significantly reduced hepatic triglyceride content, attenuated steatosis, lowered MASLD activity scores, and decreased fibrotic remodeling. Mechanistically, transcriptomic profiling, ChIP-qPCR, promoter-reporter assays, and targeted knockdown models indicated that TFEB exerts its protective effects against lipid accumulation at least partly by transcriptionally activating the fibroblast growth factor 21 (FGF21) signaling pathway. Collectively, these findings establish LNP-mediated TFEB mRNA delivery as a useful preclinical approach for investigating hepatic biology and provide a targeted, transient, and non-integrating genetic strategy with potential for the treatment of MASLD.
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BibTeX
@article{ju2026lipid,
title = {{Lipid nanoparticle-mediated transcription factor EB mRNA delivery for the treatment of metabolic dysfunction-associated steatotic liver disease.}},
author = {Wenhao Ju and Chi Zhang and Tingting Zhang and Yingjie Liu and Xingyun Wang and Linjun Zeng and Yangpo Cao and Haihuan Lin and Ouhui Li and Peng George Wang and Yunjiao He and Haocheng Lu},
journal = {Molecular biomedicine},
year = {2026},
month = oct,
doi = {10.1186/s43556-026-00615-0},
url = {https://europepmc.org/article/MED/42905254},
note = {CC BY},
}
RIS
TY - JOUR
TI - Lipid nanoparticle-mediated transcription factor EB mRNA delivery for the treatment of metabolic dysfunction-associated steatotic liver disease.
AU - Wenhao Ju
AU - Chi Zhang
AU - Tingting Zhang
AU - Yingjie Liu
AU - Xingyun Wang
AU - Linjun Zeng
AU - Yangpo Cao
AU - Haihuan Lin
AU - Ouhui Li
AU - Peng George Wang
AU - Yunjiao He
AU - Haocheng Lu
PY - 2026
DA - 2026/10/21
JO - Molecular biomedicine
DO - 10.1186/s43556-026-00615-0
UR - https://europepmc.org/article/MED/42905254
AB - Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent disorder characterized by excessive hepatic lipid accumulation, frequently progressing to steatohepatitis, fibrosis, and cirrhosis. Transcription factor EB (TFEB) coordinates lysosomal biogenesis, autophagy, and lipid catabolism, and therefore represents a potential therapeutic target; however, safe and direct strategies for selectively enhancing hepatic TFEB activity remain limited. Here, liver-targeted lipid nanoparticles (LNPs) were developed to deliver mRNAs encoding wild-type TFEB or the constitutively active TFEB S211A mutant, and their efficacy was evaluated in cellular and choline-deficient, L-amino acid-defined high-fat diet (CDAHFD)-induced mouse models of MASLD. LNP-mediated delivery increased hepatic TFEB expression, enhanced autophagic flux, and reprogrammed metabolic pathways toward fatty acid oxidation (e.g., CPT1A and ACOX1) while suppressing the expression of lipogenic genes (e.g., FASN, ACC, and SREBP1). Consequently, targeted TFEB mRNA therapy significantly reduced hepatic triglyceride content, attenuated steatosis, lowered MASLD activity scores, and decreased fibrotic remodeling. Mechanistically, transcriptomic profiling, ChIP-qPCR, promoter-reporter assays, and targeted knockdown models indicated that TFEB exerts its protective effects against lipid accumulation at least partly by transcriptionally activating the fibroblast growth factor 21 (FGF21) signaling pathway. Collectively, these findings establish LNP-mediated TFEB mRNA delivery as a useful preclinical approach for investigating hepatic biology and provide a targeted, transient, and non-integrating genetic strategy with potential for the treatment of MASLD.
SN - 2662-8651
ER -