Luo Lidan, Wang Shuai, Du Ruili, Zhong Mei, Zhu Wenli, Huang Furong, Ouyang Weijun, Huang Jinrong, Tong Guangdong
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.
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.
Eur J Pharmacol. 2025 Oct 5;1004:177971. doi: 10.1016/j.ejphar.2025.177971. Epub 2025 Jul 17.
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.
高迁移率族蛋白B1（HMGB1）是一种参与免疫炎症的关键炎症介质，通过巨噬细胞促进肝纤维化的进展。与HMGB1结合的七聚体肽（HBHP），特异性靶向其A盒结构域，通过抑制HMGB1活性发挥抗炎作用。然而，HBHP的抗炎机制是否直接归因于其与HMGB1 A盒的结合仍不清楚。本研究旨在使用四氯化碳（CCL4）诱导的大鼠肝纤维化模型研究HBHP的肝保护作用，并进一步阐明HBHP改善肝纤维化的机制，特别是通过与HMGB1 A盒结合抑制HMGB1介导的炎症反应。在CCL4诱导的大鼠模型中，HBHP有效减轻了肝脏炎症和纤维化。值得注意的是，HBHP不仅抑制了NF-κB信号通路，还降低了氧化应激并上调了抗氧化因子，包括Nrf2、血红素加氧酶-1和NADH脱氢酶醌1。在脂多糖刺激的RAW264.7巨噬细胞中，HBHP的抗炎和抗氧化作用与HMGB1抑制剂甘草酸相当。我们进一步证明，HBHP通过抑制巨噬细胞中HMGB1介导的炎症来抑制小鼠肝星状细胞的激活，从而降低α-SMA、MyD88、胶原蛋白I和TGF-β1等纤维化基因的表达。最后，我们证实HBHP通过与HMGB1的A盒特异性结合来抑制HMGB1活性。这些发现表明，HBHP通过与HMGB1 A盒结合抑制HMGB1介导的炎症来减轻肝纤维化，可能代表与炎症相关的肝脏疾病的潜在治疗靶点。
