2. Academic Validation
  3. HBHP ameliorates CCL4-induced liver fibrosis in rats by inhibiting HMGB1-mediated inflammatory response through binding to the HMGB1-A box

HBHP ameliorates CCL4-induced liver fibrosis in rats by inhibiting HMGB1-mediated inflammatory response through binding to the HMGB1-A box

  • Eur J Pharmacol. 2025 Oct 5:1004:177971. doi: 10.1016/j.ejphar.2025.177971.
Lidan Luo 1,  Shuai Wang 2,  Ruili Du 3,  Mei Zhong 1,  Wenli Zhu 4,  Furong Huang 5,  Weijun Ouyang 1,  Jinrong Huang 6,  Guangdong Tong 7
Affiliations

Affiliations

  • 1 Department of Hepatology, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, No.15, Yingchun Road, Luohu District, Guangdong, 518033, China; Shenzhen Key Laboratory of Liver Diseases of Chinese Medicine, No.15, Yingchun Road, Luohu District, Guangdong, 518033, China.
  • 2 Department of Hepatology, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, No.15, Yingchun Road, Luohu District, Guangdong, 518033, China; Faculty of Chinese Medicine and State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Avenida Wai Long, Macau, 999078, China; Shenzhen Key Laboratory of Liver Diseases of Chinese Medicine, No.15, Yingchun Road, Luohu District, Guangdong, 518033, China.
  • 3 Shenzhen Key Laboratory of Liver Diseases of Chinese Medicine, No.15, Yingchun Road, Luohu District, Guangdong, 518033, China; The First Clinical Medical College of Henan University of Chinese Medicine, No.19, Renmin Road, Jinshui District, Henan, 450003, China.
  • 4 The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, No.1 FuHua Road, Guangdong, 518033, China.
  • 5 Department of Hepatology, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, No.15, Yingchun Road, Luohu District, Guangdong, 518033, China; Faculty of Chinese Medicine and State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Avenida Wai Long, Macau, 999078, China.
  • 6 Department of Biology, University of Copenhagen, 2100 Copenhagen, Denmark. Electronic address: jinrcn@foxmail.com.
  • 7 Department of Hepatology, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, No.15, Yingchun Road, Luohu District, Guangdong, 518033, China; Faculty of Chinese Medicine and State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Avenida Wai Long, Macau, 999078, China; Shenzhen Key Laboratory of Liver Diseases of Chinese Medicine, No.15, Yingchun Road, Luohu District, Guangdong, 518033, China. Electronic address: tgd755@163.com.
PMID: 40683441 DOI: 10.1016/j.ejphar.2025.177971
Abstract

High mobility group box 1 (HMGB1) is a critical inflammatory mediator involved in immunoinflammation and contributes to the progression of liver fibrosis via macrophages. Heptamer peptides that bind to HMGB1 (HBHP), specifically targeting its A box domain, exert anti-inflammatory effects by inhibiting HMGB1 activity. However, whether the anti-inflammatory mechanism of HBHP is directly attributed to its binding to the HMGB1 A box remains unclear. This study aims to investigate the hepatoprotective effects of HBHP using a carbon tetrachloride (CCL4)-induced rat model of liver fibrosis and to further elucidate the mechanism by which HBHP ameliorates liver fibrosis, specifically by inhibiting HMGB1-mediated inflammatory responses through binding to the HMGB1 A box. In the CCL4-induced rat model, HBHP effectively attenuated hepatic inflammation and fibrogenesis. Notably, HBHP not only suppressed NF-κB signaling but also reduced oxidative stress and upregulated antioxidant factors, including Nrf2, Heme Oxygenase-1, and NADH Dehydrogenase Quinone 1. In LPS-stimulated RAW264.7 macrophages, the anti-inflammatory and antioxidant effects of HBHP were comparable to those of the HMGB1 inhibitor glycyrrhizic acid. We further demonstrated that HBHP inhibited the activation of mouse hepatic stellate cells by suppressing HMGB1-mediated inflammation in macrophages, thereby reducing the expression of fibrogenic genes such as α-SMA, MyD88, Collagen I, and TGF-β1. Finally, we confirmed that HBHP inhibits HMGB1 activity through specific binding to its A box. These findings suggest that HBHP mitigates liver fibrosis by inhibiting HMGB1-mediated inflammation via binding to the HMGB1 A box and may represent a potential therapeutic target for liver diseases associated with inflammation.

Keywords

HBHP; HMGB1; Inflammation; Liver fibrosis.

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