2. Academic Validation
  3. A novel non-nad-based PARP1 inhibitor, Japoflavone B, triggered Caspase-3/GSDME-mediated pyroptosis through ROS/p38/p53 pathway in NSCLC

A novel non-nad-based PARP1 inhibitor, Japoflavone B, triggered Caspase-3/GSDME-mediated pyroptosis through ROS/p38/p53 pathway in NSCLC

  • Chem Biol Interact. 2025 Oct 22:420:111693. doi: 10.1016/j.cbi.2025.111693.
Haoqiang Wan 1,  Jipeng Wei 2,  Yang Wang 3,  Lanlan Ge 4,  Qiaoqiao Hu 5,  Yangfang Li 6,  Boping Zhou 6,  Xiaobin Zeng 7
Affiliations

Affiliations

  • 1 Guangdong Key Laboratory of Regional Immunity and Diseases, Department of Pathogen Biology, Shenzhen University Medical School, Shenzhen, 518120, Guangdong Province, China; Center Lab of Longhua Branch and Department of Infectious Disease, Shenzhen People's Hospital (The Second Clinical Medical College of Jinan University, The First Affiliated Hospital of Southern University of Science and Technology), Shenzhen, 518020, Guangdong Province, China; Biosafety Level 3 Laboratory, Shenzhen University Medical School, Shenzhen, 518000, Guangdong Province, China. Electronic address: hqwan@szu.edu.cn.
  • 2 The Sixth Affiliated Hospital of Jinan University, Dongguan, 523576, Guangdong Province, China; Department of Neurology, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, Guangdong Province, China.
  • 3 Guangdong Key Laboratory of Regional Immunity and Diseases, Department of Pathogen Biology, Shenzhen University Medical School, Shenzhen, 518120, Guangdong Province, China.
  • 4 Center Lab of Longhua Branch and Department of Infectious Disease, Shenzhen People's Hospital (The Second Clinical Medical College of Jinan University, The First Affiliated Hospital of Southern University of Science and Technology), Shenzhen, 518020, Guangdong Province, China; Department of Pathology (Longhua Branch), Shenzhen People's Hospital (The Second Clinical Medical College of Jinan University, The First Affiliated Hospital of Southern University of Science and Technology), Shenzhen, 518020, Guangdong Province, China.
  • 5 School of Pharmaceutical Sciences, Dongguan Campus of Guangdong Medical University, Dongguan, 523808, Guangdong Province, China.
  • 6 Center Lab of Longhua Branch and Department of Infectious Disease, Shenzhen People's Hospital (The Second Clinical Medical College of Jinan University, The First Affiliated Hospital of Southern University of Science and Technology), Shenzhen, 518020, Guangdong Province, China.
  • 7 Guangdong Key Laboratory of Regional Immunity and Diseases, Department of Pathogen Biology, Shenzhen University Medical School, Shenzhen, 518120, Guangdong Province, China; Center Lab of Longhua Branch and Department of Infectious Disease, Shenzhen People's Hospital (The Second Clinical Medical College of Jinan University, The First Affiliated Hospital of Southern University of Science and Technology), Shenzhen, 518020, Guangdong Province, China; Department of Pathology (Longhua Branch), Shenzhen People's Hospital (The Second Clinical Medical College of Jinan University, The First Affiliated Hospital of Southern University of Science and Technology), Shenzhen, 518020, Guangdong Province, China; School of Pharmaceutical Sciences, Dongguan Campus of Guangdong Medical University, Dongguan, 523808, Guangdong Province, China. Electronic address: zeng.xiaobin@szhospital.com.
PMID: 40754060 DOI: 10.1016/j.cbi.2025.111693
Abstract

Pyroptosis has gotten more and more attention, in view of its link with innate immunity and disease. Most chemotherapy drugs could cause Pyroptosis through Caspase-3/GSDME pathway, which reshapes our understanding about the mechanism of Anticancer. In our previous study, we found that a novel flavonoid, Japoflavone B (JFB), exhibited an excellent activity in vitro against the growth of Cancer cells. However, the in vivo activity and molecular mechanism still need further research. Herein, JFB could particularly inhibit the proliferation of NSCLC cells, but not normal lung epithelial cells. Consistently, JFB induced inflammatory Pyroptosis through the activation of Caspase-3 and GSDME, and triggered mitochondria-mediated Apoptosis by activation of Caspases-3/7/9. Moreover, JFB could inhibit PARP1 activity, and promote DNA damage and ROS accumulation. Meanwhile, JFB was able to considerably promote p-p38 and p53 expression. Furthermore, the expression patterns of cyclins, CDKs, and CKIs was reprogrammed to induce cell cycle G2/M arrest with JFB treatment. In vivo, JFB exhibited a comparable anti-tumor activity to Dox with no significant tissue toxicity. Collectively, our data revealed that JFB promoted Caspase-3/GSDME-mediated Pyroptosis through ROS/p38/p53 pathway as a non-NAD-based PARP-1 inhibitor with high affinity and low toxicity.

Keywords

Caspase-3/GSDME; Japoflavone B; NSCLC; PARP-1; Pyroptosis; ROS/p38/p53 pathway.

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