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

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.