通过GDP-状态稳定抑制RhoA激活以缓解心力衰竭。
Xue, M., Liang, Y., Yuan, Z., Liu, X., Chang, L., Wang, Y., Xu, P., Zhang, T., Jiang, H., Zhao, Z., Liu, J., Ruan, S., Ye, T., Pang, X., Mei, W., Wang, J., Sun, X., Wang, H., Cui, J., . . . Li, H. (2026). Inhibiting RhoA Activation Via GDP-State Stabilization to Relieve Heart Failure.. Circ Res. https://doi.org/10.1161/CIRCRESAHA.125.327107
Xue M, Liang Y, Yuan Z, Liu X, Chang L, Wang Y, et al. Inhibiting RhoA Activation Via GDP-State Stabilization to Relieve Heart Failure.. Circ Res. 2026; doi: 10.1161/CIRCRESAHA.125.327107
Xue M, Liang Y, Yuan Z, et al. Inhibiting RhoA Activation Via GDP-State Stabilization to Relieve Heart Failure.[J]. Circ Res. 2026. DOI: 10.1161/CIRCRESAHA.125.327107.
@article{xue2026,
author = {Mengzhu Xue and Yingquan Liang and Zhen Yuan and Xiangning Liu and Longfeng Chang and Yongzhi Wang and Peijia Xu and Tingting Zhang and Hewei Jiang and Zijie Zhao and Jingqiu Liu and Shanshan Ruan and Tianyu Ye and Xuelian Pang and Wenyi Mei and Jiawen Wang and Xiaoqian Sun and Huijuan Wang and Jian Cui and Yao Zu and Xudong Lin and Zhenjiang Zhao and Rui Wang and Hong Huang and Cheng Luo and Shengce Tao and Jing Wang and Yajun Duan and Lili Zhu and Huifang Tang and Jian Zhang and Yong Wang and Chun Li and Honglin Li},
title = {Inhibiting RhoA Activation Via GDP-State Stabilization to Relieve Heart Failure.},
journal = {Circ Res},
year = {2026},
doi = {10.1161/CIRCRESAHA.125.327107},
note = {PMID: 41859798},
}
TY - JOUR AU - Mengzhu Xue AU - Yingquan Liang AU - Zhen Yuan AU - Xiangning Liu AU - Longfeng Chang AU - Yongzhi Wang AU - Peijia Xu AU - Tingting Zhang AU - Hewei Jiang AU - Zijie Zhao AU - Jingqiu Liu AU - Shanshan Ruan AU - Tianyu Ye AU - Xuelian Pang AU - Wenyi Mei AU - Jiawen Wang AU - Xiaoqian Sun AU - Huijuan Wang AU - Jian Cui AU - Yao Zu AU - Xudong Lin AU - Zhenjiang Zhao AU - Rui Wang AU - Hong Huang AU - Cheng Luo AU - Shengce Tao AU - Jing Wang AU - Yajun Duan AU - Lili Zhu AU - Huifang Tang AU - Jian Zhang AU - Yong Wang AU - Chun Li AU - Honglin Li TI - Inhibiting RhoA Activation Via GDP-State Stabilization to Relieve Heart Failure. T2 - Circ Res PY - 2026 DO - 10.1161/CIRCRESAHA.125.327107 AN - PMID:41859798 ER -
Given the persistently high morbidity and mortality of heart failure (HF), targeting myocardial remodeling, particularly pathological hypertrophy and fibrosis, has become a major therapeutic priority. RhoA (Ras homolog gene family member A), a small GTPase governing cytoskeletal reorganization and cell migration, plays a pivotal role in this process. However, RhoA has long been considered undruggable because of its high-affinity binding to GDP/GTP and the absence of well-defined druggable pockets. Structural analyses comparing RhoA-GTP and RhoA-GDP conformations, combined with surface plasmon resonance-based screening, were used to identify a RhoA inhibitor. The underlying mechanism was validated in cultured cells and 3-dimensional myocardial tissue models. Therapeutic efficacy was assessed across multiple species of HF models and supported by multiomics analyses linking RhoA activation to human HF. Key findings were further confirmed by multiplex immunohistochemistry and pulldown assays in human heart specimens. We identified an unrecognized cryptic pocket adjacent to GDP in RhoA. A natural product, AH001, selectively occupied this pocket and interacted with GDP, thereby stabilizing the interaction between RhoA and its endogenous inhibitor, RhoGDIα (Rho GDP-dissociation inhibitor 1). AH001 suppressed downstream signaling by reducing MRTFA (myocardin-related transcription factor A) nuclear translocation and downregulating fibrosis- and hypertrophy-related proteins. Moreover, AH001 disrupted pathological crosstalk between These findings establish pharmacological inhibition of RhoA activation as a viable strategy to mitigate myocardial remodeling in HF and provide a conceptual framework for developing reversible inhibitors against previously undruggable small GTPases.