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Background <p>Metabolic dysfunction-associated steatotic liver disease (MASLD) is a worldwide disease characterized by hepatic steatosis. γ-glutamylcysteine (γ-GC), a non-protein thiol peptide with nontoxic side effects, can alleviate insulin resistance (IR) and alcoholic liver disease (ALD). However, the role of γ-GC in MASLD remains elusive. Herein, the aim of this study was to reveal the effects and underlying molecular mechanisms of γ-GC in the progression of MASLD.</p> Methods <p>In vivo model of mice fed with high-fat diet (HFD) and in vitro model of hepatocytes treated with FFA (oleic acid/palmitic acid = 2/1) were established to examine the therapeutic effects and molecular mechanisms of γ-GC in MASLD.</p> Results <p>HFD mice develop dyslipidemia and hepatic steatosis due to obesity. Increased lipogenesis-related protein expression and aggravated fatty acid uptake are also observed in hepatocytes treated with FFA. Mechanistic studies suggest that γ-GC can alleviate hepatic lipid deposition and steatosis through balancing lipid metabolism. Importantly, γ-GC inhibits KLF10-regulated zDHHC7 transcription via activating AKT signaling, thereby suppressing zDHHC7-mediated CD36 palmitoylation and plasma membrane translocation. Ultimately, γ-GC reduces CD36-mediated fatty acid uptake and attenuates FFA-associated lipogenic signaling, resulting in the amelioration of MASLD.</p> Conclusions <p>In summary, our results support γ-GC as a candidate dipeptide for the treatment of MASLD, which alleviates hepatic lipid deposition and steatosis by inhibiting KLF10/zDHHC7-mediated CD36 palmitoylation and plasma membrane translocation through activation of AKT signaling.</p>

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γ-GC mitigates MASLD by reducing CD36 palmitoylation and plasma membrane translocation mediated by AKT/KLF10/zDHHC7 axis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月12日

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  • Jinyi Zhou,
  • Chen Yang,
  • Yangyu Guo,
  • Lishuang Zhao,
  • Shuai Lu,
  • Lan Luo,
  • Da Zhou,
  • Zhimin Yin

摘要

Background

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a worldwide disease characterized by hepatic steatosis. γ-glutamylcysteine (γ-GC), a non-protein thiol peptide with nontoxic side effects, can alleviate insulin resistance (IR) and alcoholic liver disease (ALD). However, the role of γ-GC in MASLD remains elusive. Herein, the aim of this study was to reveal the effects and underlying molecular mechanisms of γ-GC in the progression of MASLD.

Methods

In vivo model of mice fed with high-fat diet (HFD) and in vitro model of hepatocytes treated with FFA (oleic acid/palmitic acid = 2/1) were established to examine the therapeutic effects and molecular mechanisms of γ-GC in MASLD.

Results

HFD mice develop dyslipidemia and hepatic steatosis due to obesity. Increased lipogenesis-related protein expression and aggravated fatty acid uptake are also observed in hepatocytes treated with FFA. Mechanistic studies suggest that γ-GC can alleviate hepatic lipid deposition and steatosis through balancing lipid metabolism. Importantly, γ-GC inhibits KLF10-regulated zDHHC7 transcription via activating AKT signaling, thereby suppressing zDHHC7-mediated CD36 palmitoylation and plasma membrane translocation. Ultimately, γ-GC reduces CD36-mediated fatty acid uptake and attenuates FFA-associated lipogenic signaling, resulting in the amelioration of MASLD.

Conclusions

In summary, our results support γ-GC as a candidate dipeptide for the treatment of MASLD, which alleviates hepatic lipid deposition and steatosis by inhibiting KLF10/zDHHC7-mediated CD36 palmitoylation and plasma membrane translocation through activation of AKT signaling.