Novel Drug TJ0113 Induces Mitochondrial Autophagy to Ameliorate Murine ADPKD

Background: Autosomal Dominant Polycystic Kidney Disease (ADPKD) is one of the most common hereditary kidney disorders,there is an urgent need to explore safer and more effective therapeutic strategies. Recent studies have further revealed that ADPKD is not only associated with a reduction in mitochondrial number and structural damage but also with impaired mitophagy activity. This leads to the accumulation of dysfunctional mitochondria, which in turn exacerbates disease progression by promoting oxidative stress, inflammation, and cyst growth. Consequently, targeting mitophagy to restore mitochondrial homeostasis may represent a novel therapeutic approach for the treatment of ADPKD. Methods: We established a conditional Pkd1 knockout mouse model (Pkd1flox/flox; Cdh16-Cre-ERT2). To mimic the progression of ADPKD, gene deletion was induced by tamoxifen administration on postnatal day 10. Mice were randomly assigned to the following treatment groups:Wild-type (WT) groups：WT+Vehicle, WT+TJ0113 ( 10 mg/kg); Knockout (KO) groups: KO + Vehicle, KO + Tolvaptan (10mg/Kg), KO + TJ0113 ( 10 mg/kg). Mice received daily intraperitoneal injections of the corresponding treatments for 20 consecutive days. Results: 1.TJ0113 Improves Renal Phenotypes in a Mouse Model of ADPKD (Figure 1) 2.TJ0113 Enhances Mitophagy and Restores Mitochondrial Integrity in ADPKD Mice (Figure 1) 3.TJ0113 Attenuates Renal Fibrosis and Inhibits Epithelial-Mesenchymal Transition in ADPKD Mice(Figure 2) 4.TJ0113 Alleviates Renal Interstitial Inflammation in ADPKD Mice (Figure 2) Conclusion: This study demonstrates that TJ0113, can effectively enhance mitophagy activity by activating the PINK1/Parkin pathway, thereby improving mitochondrial quality control. Meanwhile, TJ0113 significantly inhibits renal fibrosis and EMT, downregulating multiple pro-inflammatory cytokine expression. It alleviates renal pathological damage and improves kidney function in a Pkd1 conditional knockout mouse model of ADPKD.