The Ameliorative Effect of C-Kit (+) Hepatic Endothelial Cells With Mertk Deficiency on Nonalcoholic Steatohepatitis

I. Study Background Non-alcoholic fatty liver disease (NAFLD) has become one of the most prevalent liver disorders globally. Despite its high incidence and severity, no effective therapeutic agents currently exist. Existing treatments focus on symptomatic relief, such as hepatoprotection and enzyme reduction, rather than addressing the underlying pathogenesis. Therefore, elucidating the mechanisms driving the progression of NAFLD-related non-alcoholic steatohepatitis (NASH) and hepatic fibrosis is critical for developing preventive, ameliorative, or even curative strategies, holding significant strategic importance.

1. Role of LSECs in NAFLD Pathogenesis:

Liver sinusoidal endothelial cells (LSECs), the primary components of the hepatic sinusoidal endothelium, form a physical barrier regulating substance exchange between the hepatic parenchyma and circulation. As highly specialized endothelial cells (ECs) and the most abundant non-parenchymal cells (NPCs) in the liver, LSECs play pivotal roles in hepatic pathophysiology. Targeting LSEC function represents a promising approach to mitigate NAFLD progression and complications. 2. Heterogeneous Transcriptomic Features of LSEC Subpopulations in NAFLD:

Single-cell RNA sequencing (scRNA-seq) enables genome-wide amplification and sequencing at the single-cell level. In the liver, hepatocytes (HCs) and NPCs exhibit marked transcriptomic heterogeneity, underpinning metabolic and functional zonation. This highlights the potential of single-cell analysis in understanding liver diseases. However, scRNA-seq studies on LSECs in NAFLD remain unexplored. 3. Hypothesis: C-Kit(+)/Gas6(-)-LSEC Subpopulation Exacerbates NAFLD via Gas6/Mertk-Mediated Regulation of PINK1 Mitophagy:

Bone marrow-derived endothelial progenitor cells (EPCs), marked by C-Kit (CD117), may express C-Kit in ECs under pathological conditions. Gas6, a ligand for TAM receptors (Tyro3, Axl, Mertk), activates downstream signaling cascades regulating cell migration, inflammation, survival, and mitophagy. In NAFLD, Gas6/Mertk exhibits cell-specific roles : Anti-inflammatory in hepatic macrophages; Pro-fibrotic in hepatic stellate cells (HSCs); Protective in hepatocytes (HCs). However, the role of Gas6/Mertk in LSECs during NAFLD remains unknown. Mitochondrial dysfunction is a hallmark of NAFLD, and impaired mitophagy (e.g., PINK1 deficiency) exacerbates hepatic inflammation, steatosis, and fibrosis. Emerging evidence suggests Gas6/Mertk enhances mitophagy to preserve mitochondrial function. For instance, Mertk-/- mice exhibit cardiomyocyte mitochondrial dysfunction, and Gas6 promotes mitophagy.