College of Pharmacy, Nantong University, Nantong, PR China.
State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, PR China.
Phytother Res. 2022 Nov;36(11):4167-4182. doi: 10.1002/ptr.7549. Epub 2022 Jul 2.
Hepatocytes has been confirmed to undergo EMT and can be converted into myofibroblasts during hepatic fibrogenesis. However, the mechanism of hepatocyte EMT regulation in hepatic fibrosis, particularly through HSP27 (human homologue of rodent HSP25), remains unclear. Mangiferin (MAN), a compound extracted from Mangifera indica L, has been reported to attenuate liver injury. This study aimed to investigate the mechanisms underlying HSP27 inhibition and the anti-fibrotic effect of MAN in liver fibrosis. Our results revealed that the expression of HSP27 was remarkably increased in the liver tissues of patients with liver cirrhosis and CCl -induced fibrotic rats. However, HSP27 shRNA treatment significantly alleviated fibrosis. Furthermore, MAN was found to inhibit CCl - and TGF-β1-induced liver fibrosis and reduced hepatocyte EMT. More importantly, MAN decreased HSP27 expression to suppress the JAK2/STAT3 pathway, and subsequently blocked TGF-β1/Smad signaling, which were consistent with its protection against CCl -induced EMT and liver fibrosis. Together, these results suggest that HSP27 may play a crucial role in hepatocyte EMT and liver fibrosis by activating JAK2/STAT3 signaling and TGF-β1/Smad pathway. The suppression of HSP27 expression by MAN may be a novel strategy for attenuating the hepatocyte EMT in liver fibrosis.
肝细胞已被证实可在肝纤维化过程中发生 EMT，并可转化为肌成纤维细胞。然而，肝纤维化中肝细胞 EMT 调控的机制，特别是通过 HSP27（啮齿动物 HSP25 的人类同源物），仍不清楚。芒果苷（MAN）是从芒果中提取的一种化合物，已被报道可减轻肝损伤。本研究旨在探讨 HSP27 抑制和 MAN 在肝纤维化中的抗纤维化作用的机制。我们的结果表明，HSP27 在肝硬化患者和 CCl4 诱导的纤维化大鼠的肝组织中表达显著增加。然而，HSP27 shRNA 处理可显著减轻纤维化。此外，MAN 被发现可抑制 CCl4 和 TGF-β1 诱导的肝纤维化，并减少肝细胞 EMT。更重要的是，MAN 降低 HSP27 表达以抑制 JAK2/STAT3 通路，进而阻断 TGF-β1/Smad 信号通路，这与其对 CCl4 诱导的 EMT 和肝纤维化的保护作用一致。综上所述，这些结果表明，HSP27 可能通过激活 JAK2/STAT3 信号通路和 TGF-β1/Smad 信号通路在肝细胞 EMT 和肝纤维化中发挥关键作用。MAN 通过抑制 HSP27 表达可能是减轻肝纤维化中肝细胞 EMT 的一种新策略。
