Therapeutic targeting of the PRMT6/FOXK1 axis restores lipid homeostasis and ameliorates hepatic steatosis and steatohepatitis in mice.
5 affiliations
- 1Laboratory of Targeted Therapy and Precision Medicine, Department of Clinical Laboratory, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China.
- 2Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China.
- 3Institute of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China.
- 4Department of Pathology, Tongren Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200335, China.
- 5Department of Bariatric and Metabolic Surgery, Department of General Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China.
Abstract
Nonalcoholic fatty liver disease (NAFLD) is emerging as the leading cause of chronic liver disease, posing a global public health challenge without available therapeutic approaches. Protein arginine methyltransferase 6 is a type I PRMT that asymmetrically dimethylates arginine residues of a variety of substrates implicated in many diseases. However, its role in NAFLD pathologies has not been clarified. In this study, we show that PRMT6 is upregulated in NAFLD and NASH of mice and human patients. Prmt6-deficient mice are protected from diet-induced hepatic steatosis, steatohepatitis, insulin resistance, and glucose tolerance. Mechanistically, PRMT6 interacts with and dimethylates Forkhead box K1 (FOXK1) at four conserved arginine residues (R161, R191, R259, and R486), maintaining its nuclear localization and transcriptional activity as a repressor/activator, inhibiting fatty acid oxidation and stimulating lipogenesis programs, respectively. PRMT6 competes with glycogen synthase kinase-3 (GSK3) for binding to FOXK1 and triggers FOXK1 methylation. This methylation prevents FOXK1 from GSK3-mediated phosphorylation, leading to its dissociation from 14-3-3, enhanced nuclear retention, and transcriptional activity. Conversely, the methylation-defective FOXK1 mutant (4RK) has the opposite effect and confers resistance to diet-induced hepatic steatosis in mice. Moreover, pharmacological inhibition of PRMT6 by EPZ020411 ameliorates NAFLD progression in mice. Thus, our study demonstrates the PRMT6-FOXK1 axis as a critical regulator of NAFLD and that targeting PRMT6 represents a novel therapeutic intervention for NAFLD.
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BibTeX
@article{sun2026therapeutic,
title = {{Therapeutic targeting of the PRMT6/FOXK1 axis restores lipid homeostasis and ameliorates hepatic steatosis and steatohepatitis in mice.}},
author = {Yang Sun and Tao Chen and Lei Zhang and Jinlin Duan and Junyan Xue and Wentao Huang and Jianzhong Di and Yonglong Zhang},
journal = {Acta pharmaceutica Sinica. B},
year = {2026},
month = aug,
doi = {10.1016/j.apsb.2026.08.003},
url = {https://europepmc.org/article/MED/42948769},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Therapeutic targeting of the PRMT6/FOXK1 axis restores lipid homeostasis and ameliorates hepatic steatosis and steatohepatitis in mice.
AU - Yang Sun
AU - Tao Chen
AU - Lei Zhang
AU - Jinlin Duan
AU - Junyan Xue
AU - Wentao Huang
AU - Jianzhong Di
AU - Yonglong Zhang
PY - 2026
DA - 2026/08/06
JO - Acta pharmaceutica Sinica. B
DO - 10.1016/j.apsb.2026.08.003
UR - https://europepmc.org/article/MED/42948769
AB - Nonalcoholic fatty liver disease (NAFLD) is emerging as the leading cause of chronic liver disease, posing a global public health challenge without available therapeutic approaches. Protein arginine methyltransferase 6 is a type I PRMT that asymmetrically dimethylates arginine residues of a variety of substrates implicated in many diseases. However, its role in NAFLD pathologies has not been clarified. In this study, we show that PRMT6 is upregulated in NAFLD and NASH of mice and human patients. Prmt6-deficient mice are protected from diet-induced hepatic steatosis, steatohepatitis, insulin resistance, and glucose tolerance. Mechanistically, PRMT6 interacts with and dimethylates Forkhead box K1 (FOXK1) at four conserved arginine residues (R161, R191, R259, and R486), maintaining its nuclear localization and transcriptional activity as a repressor/activator, inhibiting fatty acid oxidation and stimulating lipogenesis programs, respectively. PRMT6 competes with glycogen synthase kinase-3 (GSK3) for binding to FOXK1 and triggers FOXK1 methylation. This methylation prevents FOXK1 from GSK3-mediated phosphorylation, leading to its dissociation from 14-3-3, enhanced nuclear retention, and transcriptional activity. Conversely, the methylation-defective FOXK1 mutant (4RK) has the opposite effect and confers resistance to diet-induced hepatic steatosis in mice. Moreover, pharmacological inhibition of PRMT6 by EPZ020411 ameliorates NAFLD progression in mice. Thus, our study demonstrates the PRMT6-FOXK1 axis as a critical regulator of NAFLD and that targeting PRMT6 represents a novel therapeutic intervention for NAFLD.
SN - 2211-3835
SN - 2211-3843
ER -