Structure, function, regulation, evolution, and therapeutic implications of PARP14.

ADP-ribosylation (ADPr) is a posttranslational modification conserved across all domains of life that regulates a wide variety of processes. Among ADP-ribosyl transferases (ARTs) in humans, PARP14 has emerged as a key regulator involved in antiviral defense, inflammation, and DNA damage response. Recent studies have uncovered its dynamic and versatile roles in modulating DNA replication stress and DNA repair, positioning it at the intersection of genomic stability and immune regulation. Despite growing insights into its molecular functions, many aspects of PARP14-mediated signaling remain elusive. In this perspective, we explore the fundamental and emerging biological features of PARP14, highlighting its structure, function, evolution, and roles in cellular homeostasis and disease. Additionally, we discuss recent advances in targeting PARP14 for therapeutic intervention, particularly in oncology and immunology. A deeper mechanistic understanding of PARP14 function may inform the development of novel therapeutic strategies that exploit its regulatory network for clinical benefit.