Inhibition of ATP1V6G3 prompts hepatic stellate cell senescence with reducing ECM by activating Notch1 pathway to alleviate hepatic fibrosis
- Tissue Cell. 2024 Dec:91:102554. doi: 10.1016/j.tice.2024.102554.
- 1. Department Gastroenterology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, China; Department Gastroenterology, Rugao Hospital of traditional Chinese Medicine, Nantong 226500, China.
- 2. Department Gastroenterology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, China.
- 3. Department Gastroenterology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, China. Electronic address: [email protected].
- 4. Department Gastroenterology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, China. Electronic address: [email protected].
Liver fibrosis is characterized by an excessive reparative response to various etiological factors, with the activated hepatic stellate cells (aHSCs) leading to extracellular matrix (ECM) accumulation. Senescence is a stable growth arrest, and the senescence of aHSCs is associated with the degradation of ECM and the regression of hepatic fibrosis, making it a promising approach for managing hepatic fibrosis. The role and specific mechanisms by which V-Type Proton ATPase Subunit G 3 (ATP6V1G3) influences senescence in activated HSCs during liver fibrosis remain unclear. Our preliminary results reveal upregulation of ATP6V1G3 in both human fibrotic livers and murine liver fibrosis models. Additionally, ATP6V1G3 inhibition induced senescence in aHSCs in vitro. Moreover, suppressing Notch1 reversed the senescence caused by ATP6V1G3 inhibition in HSCs. Thus, targeting ATP6V1G3, which appears to drive HSCs senescence through the Notch1 pathway, emerges as a potential therapeutic strategy for hepatic fibrosis.