γ-GC mitigates MASLD by reducing CD36 palmitoylation and fatty acid uptake via AKT/KLF10/zDHHC7 axis

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a pervasive global health challenge, characterized by excessive hepatic fat accumulation. Despite its high prevalence, effective therapeutic options for MASLD remain limited, with current approaches often falling short in providing specific, targeted interventions. γ-glutamylcysteine (γ-GC), a non-protein thiol peptide, has demonstrated beneficial effects in conditions like insulin resistance and alcoholic liver disease (ALD), attributed to its nontoxic profile. However, its precise role and underlying mechanisms in mitigating MASLD progression have largely been unexplored, representing a significant gap in understanding its therapeutic potential for this widespread liver disease.

Researchers investigated the therapeutic effects and molecular mechanisms of γ-GC in MASLD using both in vivo and in vitro models. For the in vivo component, mice were fed a high-fat diet (HFD) to induce MASLD, while the in vitro model utilized hepatocytes treated with free fatty acids (FFA)—a 2:1 mixture of oleic acid and palmitic acid—to simulate steatosis. The study then examined how γ-GC treatment influenced hepatic lipid deposition, fatty acid uptake, and the expression of key proteins involved in lipid metabolism. Molecular mechanisms were probed by analyzing signaling pathways, specifically focusing on AKT activation and its downstream effects on KLF10, zDHHC7, and CD36 palmitoylation.

In the in vivo model, HFD-fed mice developed significant dyslipidemia and hepatic steatosis, mirroring human MASLD. Similarly, in vitro, FFA-treated hepatocytes exhibited increased expression of lipogenesis-related proteins and aggravated fatty acid uptake. Mechanistic investigations revealed that γ-GC treatment effectively alleviated hepatic lipid deposition and steatosis by rebalancing lipid metabolism. A crucial finding was γ-GC's ability to activate AKT signaling. This activation subsequently inhibited KLF10-regulated zDHHC7 transcription. Consequently, zDHHC7-mediated CD36 palmitoylation and its translocation to the plasma membrane were suppressed.

Ultimately, γ-GC significantly reduced CD36-mediated fatty acid uptake and attenuated FFA-associated lipogenic signaling, leading to a marked amelioration of MASLD pathology in both models.