Wang Cheng, Ye Mengling, Xu Tian, Feng Jiayi, Zhang Jiaxi, Yang Wenjuan, Fang Qian, Mei Guangbo, Zhao Xuejun, Liu Kejun, Zhou Huiqin, Yu Yaru, Peng Yujun, Kuang Na, Qiu Xuebing, Zhong Qinping, Zong Hongying, Dong Huifen, Ming Zhenping, Xiong Yan, Zhou Rui
Hubei Province Key Laboratory of Allergy and Immunology, School of Basic Medical Sciences, Wuhan University, Wuhan, Hubei, China.
Department of Medical Parasitology, School of Basic Medical Sciences, Wuhan University, Wuhan, Hubei, China.
Cell Death Dis. 2025 Aug 11;16(1):608. doi: 10.1038/s41419-025-07937-x.
Liver fibrosis is driven by the persistent activation of hepatic stellate cells (HSCs) through inflammatory factors released from various cell types, including stressed hepatocytes, yet the underlying mechanisms are not fully understood. Here, we show that minichromosome maintenance complex component 7 (MCM7) is predominantly upregulated in hepatocytes of liver fibrosis mouse models and in liver cirrhosis patients. Hepatocyte-specific overexpression of MCM7 accelerates fibrosis progression, while its knockdown mitigates it in Schistosoma japonicum- and CCl4-induced fibrosis models. Mechanistically, MCM7 interacts with SHCBP1, promoting IL11 transcription via the SHCBP1-RACGAP1-STAT3 axis. Moreover, neutralizing IL11 significantly attenuated the enhanced activation of HSCs induced by MCM7 overexpression in vitro. Additionally, recombinant human IL11 (rhIL11), which effectively inhibits endogenous IL11 signaling, significantly attenuated the exacerbation of liver fibrosis driven by MCM7 overexpression in vivo. These findings identify MCM7 in hepatocytes as a key regulator of HSC activation through IL11 and highlight its potential as a therapeutic target for liver fibrosis treatment. Liver fibrosis conditions induce upregulation of MCM7 and SHCBP1 in hepatocytes. Elevated MCM7 promotes the interaction between SHCBP1 and RACGAP1, which in turn facilitates the binding of RACGAP1 to STAT3 and induces its phosphorylation. Phosphorylated STAT3 translocates to the nucleus, activating transcription of the IL11 gene. Secreted IL11 acts in a paracrine manner to enhance hepatic stellate cell activation, further exacerbating liver fibrosis.
肝纤维化是由肝星状细胞（HSCs）通过包括应激肝细胞在内的多种细胞类型释放的炎性因子持续激活所驱动的，但其潜在机制尚未完全明确。在此，我们发现微小染色体维持复合体组分7（MCM7）在肝纤维化小鼠模型的肝细胞以及肝硬化患者中主要上调。在日本血吸虫和四氯化碳诱导的纤维化模型中，肝细胞特异性过表达MCM7会加速纤维化进程，而敲低MCM7则可减轻纤维化。机制上，MCM7与SHCBP1相互作用，通过SHCBP1-RACGAP1-STAT3轴促进IL11转录。此外，中和IL11可显著减弱体外MCM7过表达诱导的HSCs激活增强。另外，有效抑制内源性IL11信号传导的重组人IL11（rhIL11）可显著减轻体内MCM7过表达驱动的肝纤维化加重。这些发现确定肝细胞中的MCM7是通过IL11调节HSC激活的关键调节因子，并突出了其作为肝纤维化治疗靶点的潜力。肝纤维化状况可诱导肝细胞中MCM7和SHCBP1上调。升高的MCM7促进SHCBP1与RACGAP1之间的相互作用，这反过来又促进RACGAP1与STAT3结合并诱导其磷酸化。磷酸化的STAT3易位至细胞核，激活IL11基因转录。分泌的IL11以旁分泌方式作用，增强肝星状细胞激活，进一步加重肝纤维化。
