PHETA2 (PH domain containing endocytic trafficking adaptor 2) is an endocytic adaptor protein that functions primarily in receptor recycling and endosomal transport 1. The protein localizes to early endosomes, recycling endosomes, and the trans-Golgi network, where it facilitates receptor recycling from endosomes back to both the trans-Golgi network and plasma membrane 1. PHETA2 operates as a functional dimer and interacts with the inositol polyphosphate 5-phosphatase OCRL1 via a conserved binding motif, linking phosphatase activity to endocytic trafficking regulation 12. Loss-of-function studies in zebrafish demonstrate that PHETA1/2 deficiency impairs endocytosis and ciliogenesis in renal tissues, with dysregulation of cathepsin K leading to abnormal craniofacial development 3. Notably, a patient-specific R6C variant acts in a dominant-negative manner, exacerbating developmental phenotypes 3. Clinically, PHETA2 expression has emerged as a potential biomarker associated with breast cancer drug sensitivity and radiation response 4, while Mendelian randomization analysis identified PHETA2 as causally linked to lung cancer risk through immune cell-mediated mechanisms 5. These findings establish PHETA2 as a critical regulator of endocytic trafficking with relevance to developmental disorders and cancer pathogenesis.