TJ-0113

Impaired mitophagy underlies the pathophysiology of acute liver failure (ALF) and is closely associated with tissue damage and dysfunction. A novel mitophagy inducer, TJ0113, was used for treatment during ALF pathogenesis. In this study, we used a novel mitophagy inducer, TJ0113, to investigate the effects and mechanisms of TAA-induced ALF mice. The results showed that TJ0113 could enhance mitophagy through Parkin/PINK1 and ATG5 pathways, which in turn attenuated mitochondrial damage, hepatocyte apoptosis, nuclear factor (NF)-κB/NLRP3 signaling activation and inflammatory responses after TAA. Metabolomics results showed that TJ0113 mainly regulated lipid metabolism, amino acid metabolism and nucleotide metabolism in the livers of ALF mice. RNA sequencing (RNA-seq) analysis yielded that TJ0113 was involved in the development of ALF by regulating the P13K/AKT signaling pathway. The key highlight of this work is the use of an aberration-free line-scanning confocal Raman imager (AFLSCRI) to study the molecular changes in blood, liver tissue, gastrocnemius muscle, and mitochondrial extracts in ALF mice after TJ0113 treatment. Compared to the measurement with conventional assays, Raman microspectroscopy (micro-Raman) offers the benefits of being rapid, non-invasive, label-free and real-time. Our results found good agreement between Raman signals and histopathologic findings. The system has good performance with a spatial resolution of 2 μm, a spectral resolution of 4 cm^-1 and a fast detection speed improved by 2 orders. Innovations in this test contribute to clinical diagnosis of disease, personalized treatment, effective intraoperative guidance and accurate prognosis. The data may help in the development of a non-invasive clinical device for mitochondrial damage using bedside micro-Raman.

Metabolic dysfunction-associated steatohepatitis (MASH) fibrosis is a liver disease accompanied by inflammatory cell infiltration. There is growing evidence that insufficient mitophagy can exacerbate inflammation and liver fibrosis (LF). TJ0113 is a novel mitophagy inducer. The study aimed to explore the role of TJ0113 in ameliorating fibrosis in MASH and its mechanisms.

A high-fat diet (HFD)-induced MASH mice model and a transforming growth factor (TGF)-β1-induced LX-2 cells model were used, and then they were treated with TJ0113. Changes in hepatocyte damage were observed using electron microscopy. Expression of key molecules related to mitophagy, mitochondrial damage and inflammation in liver was detected by immunofluorescence staining (IF), immunohistochemistry (IHC) and western blotting (WB).

TJ0113 induces mitophagy through parkin/PINK1 and ATG5 signaling pathways and reduces lipid accumulation, inflammation and fibrosis in the liver of MASH mice. TJ0113 attenuated hepatic injury and lowered serum ALT, AST, TC and TG levels. TJ0113 reduced pro-inflammatory factors (IL-1β, IL-6, TNF-α), TGF-β1/Smad pathway activation and typical fibrosis-related molecules (α-SMA, Collagen-1) expression. In addition, NF-κB/NLRP3 signaling pathway activation after MASH was significantly attenuated by enhanced Mitophagy. We found that TJ0113 was able to effectively and safely induce mitophagy in vitro and reduce TGF-β1/Smad signaling and downstream pro-fibrotic responses in TGF-β1-treated LX-2 cells.

TJ0113 enhances mitophagy to inhibit lipid accumulation, inflammation and fibrosis formation in MASH, and is a candidate for MASH treatment.