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ATM deficiency aggravates the progression of liver fibrosis induced by carbon tetrachloride in mice

Ataxia telangiectasia mutated (ATM) is a pivotal sensor during the DNA damage response that slows cell passage through the cell cycle checkpoints to facilitate DNA repair, and liver fibrosis is an irreversible pathological consequence of the sustained wound-healing process, However, the effects of ATM on the development of liver fibrosis are still not fully understood. Therefore, the aim of the study was to investigate the effects and potential mechanisms of ATM on the progression of liver fibrosis. Wild-type and ATM-deficient were administered with carbon tetrachloride (CCl4, 5 ml/kg, i.p.) for 8 weeks to induce liver fibrosis, and the liver tissues and serum were collected for analysis. KU-55933 (10 μM) was used to investigate the effects of ATM blockage on CCl4-induced hepatocyte injury in vitro. The results showed that ATM deficiency aggravated the increased serum transaminase levels and liver MDA, HYP, and 8-OHdG contents compared with the model group (p < 0.05). Sirius red staining showed that ATM deficiency exacerbated liver collagen deposition in vivo, which was associated with the activation of TGF-β1/Smad2 signaling. Furthermore, blocking ATM with KU-55933 exacerbated the production of ROS and DNA damage caused by CCl4 exposure in HepG2 cells, and KU-55933 treatment also reversed the downregulated expression of CDK1 and CDK2 after CCl4 exposure in vitro. Moreover, the loss of ATM perturbed the regulation of the hepatic cell ChK2-CDC25A/C-CDK1/2 cascade and apoptosis in vivo, which was accompanied by increased Ki67-positive and TUNEL-positive cells after chronic CCl4 treatment. In conclusion, our results indicated that ATM might be a critical regulator of liver fibrosis progression, and the underlying mechanisms of exacerbated liver fibrosis development in ATM-deficient mice might be associated with the dysregulation of hepatic cell proliferation and apoptosis.

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S1092 KU-55933 KU-55933 is a potent and specific ATM inhibitor with IC50/Ki of 12.9 nM/2.2 nM in cell-free assays, and is highly selective for ATM as compared to DNA-PK, PI3K/PI4K, ATR and mTOR. KU‑55933 (ATM Kinase Inhibitor) inhibits the activation of autophagy‑initiating kinase ULK1 and results in a significant decrease of autophagy.

Related Targets

Autophagy ATM/ATR ULK