Activin receptor type I (ACVR1) is a transmembrane kinase receptor belonging to bone morphogenic protein receptors (BMPs). ACVR1 plays an important role in hematopoiesis and anemia via the BMP6/ACVR1/SMAD pathway, which regulates expression of hepcidin, the master regulator of iron homeostasis. Elevated hepcidin levels are inversely associated with plasma iron levels, and chronic hepcidin expression leads to iron-restricted anemia. Anemia is one of the hallmarks of myelofibrosis (MF), a bone marrow (BM) malignancy characterized by BM scarring resulting in impaired hematopoiesis, splenomegaly, and systemic symptoms. Anemia and red blood cell transfusions negatively impact MF prognosis. Among the approved JAK inhibitors (ruxolitinib, fedratinib, momelotinib, and pacritinib) for MF, momelotinib and pacritinib are preferably used in cytopenic patients; both agents are potent ACVR1 inhibitors that suppress hepcidin expression via the BMP6/ACVR1/SMAD pathway and restore iron homeostasis/erythropoiesis. In September 2023, momelotinib was approved as a treatment for patients with MF and anemia. Zilurgisertib (ACVR1 inhibitor) and DISC-0974 (anti-hemojuvelin monoclonal antibody) are evaluated in early phase clinical trials in patients with MF and anemia. Luspatercept (ACVR2B ligand trap) is assessed in transfusion-dependent MF patients in a registrational phase 3 trial. Approved ACVR1 inhibitors and novel agents in development are poised to improve the outcomes of anemic MF patients.
I型激活素受体（ACVR1）是一种属于骨形态发生蛋白受体（BMPs）家族的跨膜激酶受体。该受体通过BMP6/ACVR1/SMAD通路调控铁稳态核心调节因子铁调素的表达，在造血功能和贫血发生中发挥关键作用。铁调素水平升高与血浆铁浓度呈负相关，其长期高表达会导致铁限制性贫血。贫血是骨髓纤维化（MF）的典型特征之一，这是一种以骨髓瘢痕化为特征的骨髓恶性肿瘤，可导致造血功能受损、脾肿大及全身症状。贫血及红细胞输注需求对MF预后产生负面影响。在已获批用于MF治疗的JAK抑制剂（鲁索替尼、菲卓替尼、莫洛替尼、帕克替尼）中，莫洛替尼和帕克替尼更适用于血细胞减少患者；这两种药物均为强效ACVR1抑制剂，可通过BMP6/ACVR1/SMAD通路抑制铁调素表达，恢复铁稳态/红细胞生成。2023年9月，莫洛替尼获批用于治疗伴有贫血的MF患者。Zilurgisertib（ACVR1抑制剂）和DISC-0974（抗血幼素单克隆抗体）正在针对MF贫血患者开展早期临床试验。Luspatercept（ACVR2B配体捕获剂）正在输血依赖性MF患者中进行注册性III期试验评估。已获批的ACVR1抑制剂及在研新型药物有望改善贫血型MF患者的临床结局。
ACVR1: A Novel Therapeutic Target to Treat Anemia in Myelofibrosis
肿瘤(癌症)患者之家