PAN3 is a regulatory subunit of the PAN2-PAN3 deadenylase complex that catalyzes initial poly(A) tail shortening, a rate-limiting step in mRNA degradation 1. PAN3 enhances PAN2 deadenylase activity and modulates mRNA stability globally through multiple decay pathways, including ARE-mediated, microRNA-mediated, and nonsense-mediated decay 2. Two PAN3 isoforms (Pan3S and Pan3L) display antagonistic functions: Pan3S more strongly enhances PAN2 activity through PABP interaction, while Pan3L suppresses it, coordinating biphasic deadenylation kinetics 2. PAN3 activity is required for efficient P-body formation, cytoplasmic processing bodies where mRNAs are translationally silenced and decayed 3. The complex specifically recognizes and processes long poly(A) tails characteristic of mammalian mRNAs through an extended substrate-binding path 4. Clinically, PAN3 dysregulation has emerged in acute lymphoblastic leukemia (ALL), where deletions downstream of PAN3 at 13q12.2 result in CDX2 enhancer hijacking, defining a high-risk B-ALL subtype in young adults characterized by treatment resistance and poor prognosis 56. These findings reveal PAN3 as a critical hub integrating mRNA decay with gene regulation and disease pathogenesis.