Acvrl1, also known as Activin A receptor-like type 1 or Alk1, is a signaling receptor in the bone morphogenetic protein (BMP) pathway, which is part of the transforming growth factor-β (TGF-β) superfamily. This gene is crucial for normal vascular development, as its mutations are associated with hereditary hemorrhagic telangiectasia (HHT) [2,3,5,6,7,8]. Gene knockout models, such as the generation of a heterozygous ACVRL1(wt/mut) knockout iPS cell line, have been used to study its role in TGF-β and BMP-related angiogenesis [4].

In colorectal cancer, RNA sequencing has identified the activation of ACVRL1 under treatment with multitarget tyrosine kinase inhibitors (mTKIs). Knockdown and overexpression experiments of ACVRL1 in CRC cells have shown that it significantly affects the cells' sensitivity to mTKIs both in vitro and in vivo. Mechanistically, the β-catenin/TCF-1-KCNQ1OT1/miR-7-5p axis mediates ACVRL1 activation. ACVRL1 interacts with glutathione peroxidase 2 (GPX2), and through its association with ubiquitin-specific peptidase 15 (USP15), it deubiquinates GPX2 at the K187 site, leading to GPX2 protein accumulation. This ultimately results in increased ROS clearance, decreased cell apoptosis, and mTKI resistance [1].

In summary, Acvrl1 is essential for vascular development and its dysregulation is involved in diseases like HHT. In colorectal cancer, Acvrl1 plays a key role in the resistance to mTKIs. Studies using gene-modified models, such as the ACVRL1 knockout iPS cell line, have provided valuable insights into its functions in angiogenesis and disease-related processes [1,4].