肝星状细胞中ITGBL1-MYH9相互作用作为机械调节因子控制小鼠肝纤维化
ITGBL1-MYH9 interaction in hepatic stellate cells acts as a mechanoregulator controlling liver fibrosis in mice.
摘要(中文译文)
肝星状细胞（HSC）活化可导致肝纤维化，而目前尚无有效治疗方法。细胞骨架异常重塑是HSC活化的核心驱动力。已知非肌性肌球蛋白II（NM II）通过其肌动蛋白交联和收缩特性调控细胞骨架重塑。然而，在肝纤维化过程中调控HSC内肌动球蛋白组装和收缩力的分子因素仍鲜有明确。在此，我们发现整合素β样1（ITGBL1）通过负向调控HSC中肌动球蛋白收缩力驱动的机械转导，作为HSC静息状态的守门人。在患者和小鼠纤维化肝脏中的活化HSC中，ITGBL1表达显著升高。出乎意料的是，HSC特异性Itgbl1缺失加重了肝纤维化，而HSC中ITGBL1过表达则限制了肝纤维化，提示ITGBL1对致病性HSC活化具有保护作用。多组学和功能分析揭示，ITGBL1通过破坏依赖于肌球蛋白重链9（MYH9，也称为NM II重链A）的肌动球蛋白组装，损害了HSC中F-肌动蛋白丝的组织。与此一致，HSC特异性Myh9缺失或HSC中Myh9沉默减轻了肝纤维化。综上所述，我们的研究揭示了ITGBL1-MYH9相互作用作为一个关键的机械调控制动器，维持HSC的细胞骨架平衡和机械稳态，为对抗肝纤维化提供了有前景的治疗策略。
Abstract
Hepatic stellate cell (HSC) activation can lead to liver fibrosis, for which there are no effective treatments. Aberrant cytoskeletal reorganization is a central driver of HSC activation. Non-muscle myosin II (NM II) is known to regulate cytoskeleton remodeling via its actin cross-linking and contractile properties. However, the molecular players controlling actomyosin assembly and contractility in HSCs during liver fibrosis remain poorly defined. Here, we identified integrin β-like 1 (ITGBL1) as a gatekeeper of HSC quiescence by negatively regulating actomyosin contractility-driven mechanotransduction in HSCs. ITGBL1 expression was markedly elevated in activated HSCs found in patient and mouse fibrotic livers. Unexpectedly, HSC-specific Itgbl1 deficiency worsened liver fibrosis, whereas ITGBL1 overexpression in HSCs limited it, suggesting a protective role for ITGBL1 against a pathogenic HSC activation. Multiomics and functional analyses revealed that ITGBL1 impaired F-actin filament organization in HSCs by disrupting actomyosin assembly dependent on myosin heavy chain 9 (MYH9, also named NM II heavy chain A). In line, HSC-specific Myh9 deficiency or silencing of Myh9 in HSCs alleviated liver fibrosis. Taken together, our findings unveil that ITGBL1-MYH9 interaction acts as a critical mechanoregulatory brake that maintains cytoskeletal equilibrium and mechanical homeostasis in HSCs, providing a promising therapeutic strategy to combat liver fibrosis.
如何引用
AMA
Yixin Li, Yan Wang, Chenhao Tong, Xinghuan Fu, Ningning Ma, Yawen Hao, et al. ITGBL1-MYH9 interaction in hepatic stellate cells acts as a mechanoregulator controlling liver fibrosis in mice.. The Journal of clinical investigation. 2026; doi:10.1172/JCI203412.
APA
Yixin Li, Yan Wang, Chenhao Tong, Xinghuan Fu, Ningning Ma, Yawen Hao, et al (2026). ITGBL1-MYH9 interaction in hepatic stellate cells acts as a mechanoregulator controlling liver fibrosis in mice.. The Journal of clinical investigation. https://doi.org/10.1172/JCI203412
GB/T 7714
Yixin Li, Yan Wang, Chenhao Tong, Xinghuan Fu, Ningning Ma, Yawen Hao, et al. ITGBL1-MYH9 interaction in hepatic stellate cells acts as a mechanoregulator controlling liver fibrosis in mice.[J]. The Journal of clinical investigation, 2026 doi:10.1172/JCI203412.
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