Chronic graft-versus-host disease (cGVHD) is an immune-mediated disorder characterized by chronic inflammation and fibrosis. Rho-associated coiled-coil–containing protein kinases (ROCKs) are key coordinators of tissue response to injury, regulating multiple functions, such as gene expression and cell migration, proliferation and survival. Relevant to cGVHD and autoimmunity, only the ROCK2 isoform drives a pro-inflammatory type 17 helper T (Th17) cell response. Moreover, ROCK2 inhibition shifts the Th17/regulatory T (Treg) cell balance toward Treg cells and restores immune homeostasis in animal models of autoimmunity and cGVHD. Furthermore, the selective inhibition of ROCK2 by belumosudil reduces fibrosis by downregulating both transforming growth factor-β signaling and profibrotic gene expression, thereby impeding the creation of focal adhesions. Consistent with its anti-inflammatory and antifibrotic activities, belumosudil has demonstrated efficacy in clinical studies, resulting in an overall response rate of >70% in patients with cGVHD who failed 2 to 5 prior lines of systemic therapy. In summary, selective ROCK2 inhibition has emerged as a promising novel therapeutic approach for treating cGVHD and other immunologic diseases with unique mechanisms of action, targeting both immune imbalance and detrimental fibrotic responses.

慢性移植物抗宿主病（cGVHD）是一种免疫介导的疾病，其特征是慢性炎症和纤维化。 Rho 相关卷曲螺旋蛋白激酶 (ROCK) 是组织对损伤反应的关键协调者，调节多种功能，例如基因表达和细胞迁移、增殖和存活。与 cGVHD 和自身免疫相关，只有 ROCK2 同工型可驱动促炎 17 型辅助 T (Th17) 细胞反应。此外，ROCK2 抑制可将 Th17/调节性 T (Treg) 细胞平衡转向 Treg 细胞，并恢复自身免疫和 cGVHD 动物模型中的免疫稳态。此外，belumosudil 对 ROCK2 的选择性抑制通过下调转化生长因子-β 信号传导和促纤维化基因表达来减少纤维化，从而阻止粘着斑的产生。与其抗炎和抗纤维化活性一致，belumosudil 在临床研究中已证明有效，对于既往 2 至 5 线全身治疗失败的 cGVHD 患者，总体缓解率 > 70%。总之，选择性 ROCK2 抑制已成为治疗 cGVHD 和其他免疫性疾病的一种有前途的新型治疗方法，具有独特的作用机制，针对免疫失衡和有害的纤维化反应。