Mertk+ Liver Sinusoidal Endothelial Cells Negatively Regulate PINK1 Related Mitophagy and Accelerate MASH
- Immun Inflamm Dis. 2025 Sep;13(9):e70256. doi: 10.1002/iid3.70256.
- 1. Department of Gastroenterology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China.
- 2. Ningde Clinical Medical College of Fujian Medical University, Ningde, Fujian, China.
- 3. Ningde Municipal Hospital of Ningde Normal University, Ningde, Fujian, China.
- 4. Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiaotong University, School of Medicine, Shanghai, China.
Background: Mer tyrosine kinase (Mertk) regulating mitochondrial function of liver sinusoidal endothelial cells (LSECs) in metabolic dysfunction-associated steatohepatitis (MASH) remains unclear.
Methods: Mertk/p-Mertk, PINK1, and ERK/p-ERK expression in steatotic LSECs and livers of MASH mice were studied. Mitochondrial functions were assessed via immunofluorescence, Western blot, and qPCR. c-Kit+-bone marrow cells (BMCs)sh-Mertk were bone marrow transplanted (BMT) to MASH mice to evaluate its effect.
Results: Ov-Mertk would markedly stimulate ERK, and ERK further suppress downstream PINK1. Higher levels of Mertk/p-Mertk and lower levels of PINK1 were confirmed in steatotic LSECs and MASH mice livers. Steatotic LSECssh-Mertk exhibited intact Mitophagy, integral mitochondrial membrane potential, reduced reactive oxygen productions and upregulation of the PINK1 pathway. BMT of c-Kit+-BMCssh-Mertk could equivalently protect mitochondrial functions and ameliorate lipid accumulation in MASH mice.
Conclusion: Mertk negatively regulates PINK1-mediated Mitophagy in LSECs through the p-ERK signaling pathway, thereby accelerating MASH progression. Therefore, LSECs deficient of Mertk should be a novel therapy for reversing PINK1-related Mitophagy and MASH.