2. Academic Validation
  3. Inhibition of Rho GEFs attenuates pulmonary fibrosis through suppressing myofibroblast activation and reprogramming profibrotic macrophages

Inhibition of Rho GEFs attenuates pulmonary fibrosis through suppressing myofibroblast activation and reprogramming profibrotic macrophages

  • Cell Death Dis. 2025 Apr 11;16(1):278. doi: 10.1038/s41419-025-07573-5.
Chengju Luo # 1 2,  Chenqi Huang # 1,  Yuqi Zhu # 3,  Yuxin Zhou 1,  Yansheng Qiao 1,  Chenxiao Shi 1,  Yuan Gao 4,  Yongjian Guo 5,  Libin Wei 6
Affiliations

Affiliations

  • 1 Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, #24 Tongjiaxiang, Nanjing, 210009, China.
  • 2 Department of Pharmacy, Affiliated Hospital of Nantong University, Nantong, 226001, China.
  • 3 Bayi Hospital Affiliated to Nanjing University of Chinese Medicine, #138 Xianlin Rd, Nanjing, 210023, China.
  • 4 Public Laboratory Platform, China Pharmaceutical University, #24 Tongjiaxiang, Nanjing, 210009, China.
  • 5 School of Biopharmacy, China Pharmaceutical University, #639 Longmian Avenue, Nanjing, 211198, China. guoyj@cpu.edu.cn.
  • 6 Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, #24 Tongjiaxiang, Nanjing, 210009, China. wlbiws_1986@aliyun.com.
  • # Contributed equally.
PMID: 40216763 DOI: 10.1038/s41419-025-07573-5
Abstract

Idiopathic pulmonary fibrosis has a poor prognosis, with existing medications only partially alleviating symptoms, highlighting the urgent need for new therapeutic approaches. The dysregulations of Rho GTPases/ROCK are related with various diseases, including fibrosis. Nevertheless, the development of drugs for pulmonary fibrosis treatment has predominantly concentrated on ROCK inhibitors. Small GTPases have been historically recognized as "undruggable". Here, we explore a novel Rho GEFs inhibitor GL-V9, and find that GL-V9 alleviates bleomycin-induced pulmonary fibrosis in mice by inhibiting myofibroblast activation and reprogramming profibrotic macrophages. Distinct from the mechanisms of the first-line drug Nintedanib, GL-V9 binds to the DH/PH domain of Rho GEFs and block the activation of Rho GTPase signaling. This action subsequently suppresses myofibroblast activation by interfering with Rho GTPase-dependent cytoskeletal reorganization and the activity of MRTF and YAP, and inhibits M2 macrophage polarization by modulating RhoA/STAT3 activity. The discovery of new regulatory mechanisms of GL-V9 suggests that targeting Rho GEFs represents a potent strategy for pulmonary fibrosis treatment.

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