Related Experiment Video

Updated: Jan 30, 2026

Mouse Model of Metabolic Dysfunction-Associated Steatotic Liver Disease with Fibrosis
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Mouse Model of Metabolic Dysfunction-Associated Steatotic Liver Disease with Fibrosis

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TM4SF5-mediated KEAP1 Regulation in Hepatocytes Irrelevant to NRF2 Expression and Activity Promotes Oxidative Stress

Eun-Ae Shin1,2, Haesong Lee1,2, Kyung-Hee Pyo1,2

  • 1Department of Pharmacy, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea.

International Journal of Biological Sciences
|January 29, 2026
PubMed

Insights

Transmembrane 4 L six family member 5 (TM4SF5) influences metabolic dysfunction-associated steatohepatitis (MASH) by regulating KEAP1 stability, independent of NRF2. This TM4SF5-KEAP1 interaction is a potential therapeutic target for MASH.

Area of Science:

  • Hepatology
  • Molecular Biology
  • Biochemistry

Background:

  • Metabolic dysfunction-associated steatohepatitis (MASH)-associated fibrosis involves inflammation, oxidative stress from reactive oxygen species (ROS), abnormal lipid metabolism, and extracellular matrix (ECM) deposition.
  • The NRF2-KEAP1 pathway is crucial for regulating ROS levels.
  • Transmembrane 4 L six family member 5 (TM4SF5) is linked to metabolic dysfunction-associated steatotic liver disease (MASLD), but its role in lipid and ROS accumulation during MASLD is unclear.

Purpose of the Study:

  • To investigate how hepatocyte TM4SF5 influences the NRF2-KEAP1 pathway in the context of MASLD.
  • To determine the mechanism by which TM4SF5 affects KEAP1 stability and its downstream consequences.

Main Methods:

  • Utilized various in vitro and in vivo MASLD models.
  • Assessed the interaction between TM4SF5 and KEAP1 using wild-type and knockout mice (Tm4sf5-/-).
  • Examined the effects of TM4SF5 and KEAP1 modulation on MASLD phenotypes, including lipid accumulation, oxidative stress, and inflammation.

Main Results:

  • Hepatocyte TM4SF5 exhibits biphasic regulation of KEAP1: downregulation in physiological states and stabilization in pathological conditions, without affecting NRF2 levels.
  • TM4SF5 binds to KEAP1 via its cytosolic C-terminus, promoting KEAP1 proteasomal degradation.
  • TM4SF5-mediated KEAP1 stabilization contributes to increased CD36 levels, oxidative stress, and hepatic inflammation in hyperlipidemic MASLD models.
  • Genetic alterations in Tm4sf5 and Nrf2 confirmed TM4SF5-induced MASLD phenotypes characterized by elevated Keap1, independent of Nrf2 activity.
  • Suppression of KEAP1 alone reversed the MASLD-promoting effects of TM4SF5.

Conclusions:

  • TM4SF5 modulates KEAP1 stability independently of NRF2.
  • TM4SF5-mediated KEAP1 stabilization is a key driver of MASLD progression.
  • Targeting the TM4SF5-KEAP1 interaction presents a potential therapeutic strategy for MASH and MASLD.
Keywords:
KEAP1lipid toxicitymetabolic dysfunction-associated steatohepatitisreactive oxygen speciestetraspanin

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