Evidence map›Paper›PMID 41859798›Full record

ArticleCirculation research2026

Inhibiting RhoA Activation Via GDP-State Stabilization to Relieve Heart Failure.

Mengzhu Xue, Yingquan Liang, Zhen Yuan, Xiangning Liu, Longfeng Chang, Yongzhi Wang, Peijia Xu, Tingting Zhang, Hewei Jiang, Zijie Zhao and 24 more

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Article in Circulation research, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.

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2citing papers in PubMed
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3 · Its place in the literature

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2 citing papers in PubMed.

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5 · Who and what money

Authors and funding

34 authors.

Mengzhu Xue *Innovation Center for AI and Drug Discovery, School of Pharmacy, East China Normal University, Shanghai, China (M.X., Y.L., L.C., Yongzhi Wang, P.X., T.Z., H.L.).
Yingquan Liang *Innovation Center for AI and Drug Discovery, School of Pharmacy, East China Normal University, Shanghai, China (M.X., Y.L., L.C., Yongzhi Wang, P.X., T.Z., H.L.).
Zhen Yuan *Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science & Technology, China (Z.Y., L.C., Yongzhi Wang, S.R., T.Y., X.P., W.M., Jiawen Wang, Zhenjiang Zhao, R.W., L.Z., J.Z., H.L.).ORCID 0000-0001-7106-4632
Xiangning Liu *Modern Research Center for Traditional Chinese Medicine, Key Laboratory of TCM Syndrome and Formula, Ministry of Education, School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, China (X. Liu, C. Li).ORCID 0000-0003-2829-7507
Longfeng Chang *Innovation Center for AI and Drug Discovery, School of Pharmacy, East China Normal University, Shanghai, China (M.X., Y.L., L.C., Yongzhi Wang, P.X., T.Z., H.L.).ORCID 0009-0006-5396-4833
Yongzhi Wang *Innovation Center for AI and Drug Discovery, School of Pharmacy, East China Normal University, Shanghai, China (M.X., Y.L., L.C., Yongzhi Wang, P.X., T.Z., H.L.).
Peijia XuInnovation Center for AI and Drug Discovery, School of Pharmacy, East China Normal University, Shanghai, China (M.X., Y.L., L.C., Yongzhi Wang, P.X., T.Z., H.L.).
Tingting ZhangInnovation Center for AI and Drug Discovery, School of Pharmacy, East China Normal University, Shanghai, China (M.X., Y.L., L.C., Yongzhi Wang, P.X., T.Z., H.L.).
Hewei JiangLingang Laboratory, Shanghai, China (H.J.).
Zijie ZhaoState Key Laboratory of Natural and Biomimetic Drugs, Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University, Beijing, China (Zijie Zhao, Jing Wang).
Jingqiu LiuDrug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences (J.L., C. Luo).
Shanshan RuanShanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science & Technology, China (Z.Y., L.C., Yongzhi Wang, S.R., T.Y., X.P., W.M., Jiawen Wang, Zhenjiang Zhao, R.W., L.Z., J.Z., H.L.).ORCID 0009-0001-5275-9225
Tianyu YeShanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science & Technology, China (Z.Y., L.C., Yongzhi Wang, S.R., T.Y., X.P., W.M., Jiawen Wang, Zhenjiang Zhao, R.W., L.Z., J.Z., H.L.).
Xuelian PangShanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science & Technology, China (Z.Y., L.C., Yongzhi Wang, S.R., T.Y., X.P., W.M., Jiawen Wang, Zhenjiang Zhao, R.W., L.Z., J.Z., H.L.).
Wenyi MeiShanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science & Technology, China (Z.Y., L.C., Yongzhi Wang, S.R., T.Y., X.P., W.M., Jiawen Wang, Zhenjiang Zhao, R.W., L.Z., J.Z., H.L.).
Jiawen WangShanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science & Technology, China (Z.Y., L.C., Yongzhi Wang, S.R., T.Y., X.P., W.M., Jiawen Wang, Zhenjiang Zhao, R.W., L.Z., J.Z., H.L.).
Xiaoqian SunState Key Laboratory of Traditional Chinese Medicine Syndrome, Guangzhou University of Chinese Medicine, Guangdong, China (X.S., H.W., C. Li).ORCID 0000-0003-3065-4817
Huijuan WangState Key Laboratory of Traditional Chinese Medicine Syndrome, Guangzhou University of Chinese Medicine, Guangdong, China (X.S., H.W., C. Li).ORCID 0009-0004-7932-7897
Jian CuiKey Laboratory of Multi-omics And Artificial Intelligence of Cardiovascular Diseases, University of South China, Clinical Research Center for Myocardial Injury in Hunan Province, Hengyang, Hunan, China (J.C., H.H., H.T.).
Yao ZuCollege of Fisheries and Life Science, Shanghai Ocean University, Shanghai, China (Y.Z.).ORCID 0000-0001-8081-9136
Xudong LinGuangdong Provincial Key Laboratory of Sensor Technology and Biomedical Instrument School of Biomedical Engineering, Shenzhen Campus of Sun Yat-sen University, Shenzhen, China (X. Lin).
Zhenjiang ZhaoShanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science & Technology, China (Z.Y., L.C., Yongzhi Wang, S.R., T.Y., X.P., W.M., Jiawen Wang, Zhenjiang Zhao, R.W., L.Z., J.Z., H.L.).
Rui WangShanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science & Technology, China (Z.Y., L.C., Yongzhi Wang, S.R., T.Y., X.P., W.M., Jiawen Wang, Zhenjiang Zhao, R.W., L.Z., J.Z., H.L.).
Hong HuangKey Laboratory of Multi-omics And Artificial Intelligence of Cardiovascular Diseases, University of South China, Clinical Research Center for Myocardial Injury in Hunan Province, Hengyang, Hunan, China (J.C., H.H., H.T.).
Cheng LuoDrug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences (J.L., C. Luo).
Shengce TaoShanghai Center for Systems Biomedicine, Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Jiao Tong University, China (S.T.).ORCID 0000-0002-9210-1823
Jing WangState Key Laboratory of Natural and Biomimetic Drugs, Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University, Beijing, China (Zijie Zhao, Jing Wang).ORCID 0000-0001-7004-2247
Yajun DuanDivision of Life Sciences and Medicine, Department of Cardiology, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei (Y.D.).ORCID 0000-0002-3880-9070
Lili ZhuShanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science & Technology, China (Z.Y., L.C., Yongzhi Wang, S.R., T.Y., X.P., W.M., Jiawen Wang, Zhenjiang Zhao, R.W., L.Z., J.Z., H.L.).ORCID 0000-0003-1957-973X
Huifang TangKey Laboratory of Multi-omics And Artificial Intelligence of Cardiovascular Diseases, University of South China, Clinical Research Center for Myocardial Injury in Hunan Province, Hengyang, Hunan, China (J.C., H.H., H.T.).
Jian ZhangShanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science & Technology, China (Z.Y., L.C., Yongzhi Wang, S.R., T.Y., X.P., W.M., Jiawen Wang, Zhenjiang Zhao, R.W., L.Z., J.Z., H.L.).ORCID 0000-0002-0520-3275
Yong WangDongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China (Yong Wang).ORCID 0000-0003-3652-8037
Chun LiModern Research Center for Traditional Chinese Medicine, Key Laboratory of TCM Syndrome and Formula, Ministry of Education, School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, China (X. Liu, C. Li).
Honglin LiInnovation Center for AI and Drug Discovery, School of Pharmacy, East China Normal University, Shanghai, China (M.X., Y.L., L.C., Yongzhi Wang, P.X., T.Z., H.L.).ORCID 0000-0003-2270-1900

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

backgroundGiven 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.

methodsStructural 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.

resultsWe 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

conclusionsThese 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.

Indexed as

Guanosine DiphosphateHeart FailurerhoA GTP-Binding ProteinAnimalsEnzyme ActivationHumansMaleMiceMyocytes, CardiacRatsrho Guanine Nucleotide Dissociation Inhibitor alphaVentricular RemodelingGuanosine DiphosphaterhoA GTP-Binding ProteinRHOA protein, humanrho Guanine Nucleotide Dissociation Inhibitor alphadrug therapyfibrosisheart failurehypertrophymultiomics

Identifiers

PMID41859798

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