PDCL3 (phosducin-like 3) is a multifunctional chaperone protein with primary roles in angiogenesis and cytoskeletal regulation. Its primary function involves stabilizing the angiogenic receptor VEGFR-2 by binding to its juxtamembrane domain and inhibiting ubiquitination-mediated degradation, thereby increasing VEGFR-2 abundance and promoting VEGF-induced receptor phosphorylation 1. PDCL3 expression is regulated by hypoxia and undergoes N-terminal methionine acetylation, modifications affecting its stability and VEGFR-2 interaction 2. Mechanistically, PDCL3 also inhibits the folding activity of the chaperonin-containing T-complex (CCT), suppressing actin cytoskeleton organization 3. Clinically, PDCL3 demonstrates significant disease relevance across multiple conditions. Loss-of-function mutations in PDCL3 cause megacystis-microcolon-intestinal-hypoperistalsis syndrome (MMIHS), a severe congenital visceral myopathy affecting smooth muscle contractility 3. PDCL3 upregulation promotes glioma progression by enhancing VEGFR-2 expression and activating the VEGF signaling pathway, correlating with poor prognosis 45. Genome-wide association studies identified PDCL3 variants associated with Alzheimer's disease risk 6. In colorectal cancer, PDCL3 emerges as a protective prognostic factor within cuproptosis and disulfidptosis pathways 7. Overall, PDCL3 functions as a context-dependent regulator—protective in inherited visceral diseases and colorectal cancer but promoting pathological angiogenesis in glioma.