2. Academic Validation
  3. Hinokiflavone exerts dual regulation on apoptosis and pyroptosis via the SIX4/Stat3/Akt pathway to alleviate APAP-induced liver injury

Hinokiflavone exerts dual regulation on apoptosis and pyroptosis via the SIX4/Stat3/Akt pathway to alleviate APAP-induced liver injury

  • Life Sci. 2024 Oct 1:354:122968. doi: 10.1016/j.lfs.2024.122968.
Yi-Ying Liu 1,  Yang Zhang 2,  Guan-Yue Shan 3,  Jun-Ya Cheng 4,  Hui Wan 3,  Yu-Xin Zhang 3,  Hai-Jun Li 5
Affiliations

Affiliations

  • 1 Department of Transplantation Immunology, Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, Jilin Province 130061, China; Department of Biopharmacy, Jilin University School of Pharmaceutical Sciences, Changchun, Jilin Province 130021, China.
  • 2 Department of Biopharmacy, Jilin University School of Pharmaceutical Sciences, Changchun, Jilin Province 130021, China.
  • 3 Department of Transplantation Immunology, Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, Jilin Province 130061, China.
  • 4 Department of Transplantation Immunology, Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, Jilin Province 130061, China; Department of Bioengineering, Jilin University School of Pharmaceutical Sciences, Changchun, Jilin Province, 130021, China.
  • 5 Department of Transplantation Immunology, Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, Jilin Province 130061, China. Electronic address: hjli2012@jlu.edu.cn.
PMID: 39147316 DOI: 10.1016/j.lfs.2024.122968
Abstract

Hinokiflavone (HF), classified as a flavonoid, is a main bioactive compound in Platycladus orientalis and Selaginella. HF exhibits activities including anti-HIV, anti-inflammatory, Antiviral, antioxidant and anti-tumor effects. The study aimed to explore the function and the mechanisms of HF on acetaminophen (APAP)-induced acute liver injury. Results indicated that HF treatment mitigated the impact of APAP on viability and restored levels of MDA, GSH and SOD on HepG2 cells. The accumulation of Reactive Oxygen Species (ROS) mitochondrial membrane potential (MMP) in HepG2 cells stimulated by APAP were also blocked by HF. HF reduced the levels of pro-apoptotic and pro-pyroptotic proteins. Flow cytometry analysis and fluorescence staining results were consistent with western blot analysis. Following HF treatment in the APAP-induced cell model, there was observed an augmentation in the phosphorylation of STAT3 and an increase in the expression of SIX4. However, not only silenced the SIX4 protein in HepG2 cells by siRNA, but also adding the STAT3 Inhibitor (Stattic), attenuated the anti-apoptotic and anti-pyroptotic effects of HF significantly. Furthermore, HF alleviated liver damage in C57BL/6 mice model. Overall, our study demonstrated that HF mitigates Apoptosis and Pyroptosis induced by APAP in drug-induced liver injury (DILI) through the SIX4/Akt/STAT3 pathway in vivo and in vitro. HF may have promising potential for for the treatment of DILI.

Keywords

Acetaminophen; Apoptosis; DILI; Hinokiflavone; Pyroptosis.

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