2. Academic Validation
  3. The Jieduan-Niwan Formula Reduces Inflammatory Responses in Acute-on-Chronic Liver Failure Rats by Inhibiting HMGB1-Induced Hepatocyte Pyroptosis

The Jieduan-Niwan Formula Reduces Inflammatory Responses in Acute-on-Chronic Liver Failure Rats by Inhibiting HMGB1-Induced Hepatocyte Pyroptosis

  • Drug Des Devel Ther. 2025 Apr 2:19:2503-2517. doi: 10.2147/DDDT.S488659.
Weixin Hou 1 2,  Peng Fang 3,  Jiajun Liang 4,  Xiaoyi Wei 5,  Chongyang Ma 6 7,  Yanbin Gao 8 9,  Qiuyun Zhang # 6 7,  Jingnan Li # 1 2
Affiliations

Affiliations

  • 1 Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, People's Republic of China.
  • 2 Key Laboratory of Gut Microbiota Translational Medicine Research, Chinese Academy of Medical Sciences, Beijing, People's Republic of China.
  • 3 Department of Infectious Diseases, First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang Province, People's Republic of China.
  • 4 Department of Hepatology, Southern Medical University Hospital of Integrated Traditional Chinese and Western Medicine, Guangzhou, Guangdong province, People's Republic of China.
  • 5 Office of Science and Technology Administration, Beijing Friendship Hospital, Capital Medical University, Beijing, People's Republic of China.
  • 6 Department of Hepatology, School of Traditional Chinese Medicine, Capital Medical University, Beijing, People's Republic of China.
  • 7 Department of Hepatology, Beijing Key Laboratory of Traditional Chinese Medicine Collateral Disease Theory Research, Capital Medical University, Beijing, People's Republic of China.
  • 8 Department of Endocrinology, School of Traditional Chinese Medicine, Capital Medical University, Beijing, People's Republic of China.
  • 9 Department of Endocrinology, Beijing Key Laboratory of Traditional Chinese Medicine Collateral Disease Theory Research, Capital Medical University, Beijing, People's Republic of China.
  • # Contributed equally.
PMID: 40190810 DOI: 10.2147/DDDT.S488659
Abstract

Background: Acute-on-chronic liver failure (ACLF) is a global intractable disease. HMGB1-induced hepatocyte Pyroptosis expanding inflammatory responses contributes to the pathogenesis of ACLF. The JDNW formula (JDNWF) has a significant clinical effect on ACLF, but its hepatoprotective mechanisms remain elusive.

Purpose: To explore the potential molecular mechanisms of the JDNWF in ACLF by HMGB1-induced hepatocyte Pyroptosis.

Methods: Rats were divided into normal, ACLF, Caspase-1 inhibitor, HMGB1 inhibitor, JDNW, JDNW+Caspase-1 inhibitor and JDNW+HMGB1 inhibitor groups. The ACLF rat model was established by 40% carbon tetrachloride-induced liver fibrosis, followed by intraperitoneal injection of D-galactosamine and lipopolysaccharide. The liver function, coagulation function, liver pathological damage and ultrastructural changes of hepatocytes were evaluated. Triple-immunostaining of active Caspase-1, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and albumin were performed to evaluate the percentage of pyroptotic hepatocytes. Western blot, immunofluorescence, enzyme-linked immunosorbent assay (ELISA) and quantitative Real-Time PCR (RT-qPCR) were used to analyze the expressions of key genes and proteins in HMGB1-induced Pyroptosis pathways and the level of inflammatory factors.

Results: The JDNWF improved liver function, coagulation function and liver pathological damage, reduced the percentage of pyroptotic hepatocytes and inflammatory responses, and down-regulated the expressions of key genes and proteins in the HMGB1-induced Pyroptosis pathways in ACLF rats. The effect of the JDNWF was better than those of HMGB1 inhibitor (glycyrrhizin) and Caspase-1 inhibitor (VX-765). Compared with glycyrrhizin or VX-765, there were no significant differences in the above indicators after the JDNWF in combination with glycyrrhizin or VX-765. These results indicated that the JDNWF inhibited hepatocyte Pyroptosis and liver inflammation in ACLF rats through the HMGB1-induced Pyroptosis pathways.

Conclusion: The JDNWF protects the livers of ACLF rats by inhibiting HMGB1-induced hepatocyte Pyroptosis reducing inflammatory responses, suggesting that HMGB1-induced hepatocyte Pyroptosis may be a potential therapeutic target of ACLF.

Keywords

ACLF treatment; HMGB1; inflammatory response; pharmacological effect; pyroptosis; traditional Chinese medicine.

Figures
Products