2. Academic Validation
  3. PARPs and PARP inhibitors: molecular mechanisms and clinical applications

PARPs and PARP inhibitors: molecular mechanisms and clinical applications

  • Mol Biomed. 2025 Dec 29;6(1):152. doi: 10.1186/s43556-025-00385-1.
Fei Wang # 1,  Zhuyi Guo # 2,  Michael J Carr 3 4,  Weifeng Shi 5 6 7
Affiliations

Affiliations

  • 1 Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 2 Shanghai Institute of Virology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 3 National Virus Reference Laboratory, School of Medicine, University College Dublin, Dublin, D04 E1W1, Ireland.
  • 4 International Collaboration Unit, International Institute for Zoonosis Control, Hokkaido University, Sapporo, 001-0020, Japan.
  • 5 Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. [email protected].
  • 6 Shanghai Institute of Virology, Shanghai Jiao Tong University School of Medicine, Shanghai, China. [email protected].
  • 7 School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China. [email protected].
  • # Contributed equally.
PMID: 41460301 DOI: 10.1186/s43556-025-00385-1
Abstract

Poly (ADP-ribose) polymerases (PARPs) are a diverse family of Enzymes that regulate genome stability, cell death, and stress responses through ADP-ribosylation. Among them, PARP1, PARP2, and PARP3 are central to cellular DNA repair, while tankyrases, and their isoforms, contribute to telomere maintenance, transcriptional regulation, immune signaling, and metabolism. Dysregulated PARP activity drives genomic instability, Apoptosis, parthanatos, and tumor microenvironment remodeling, thereby linking PARPs to oncogenesis, immune escape, and therapy resistance. Clinically, PARP inhibitors (PARPi), such as olaparib, niraparib, rucaparib, and talazoparib, exploit synthetic lethality in homologous recombination-deficient tumors and are increasingly applied in ovarian, breast, prostate, and pancreatic cancers. Beyond oncology, preclinical studies demonstrate Antiviral efficacy of PARPi against hepatitis B virus, human immunodeficiency virus, and coronaviruses, and also therapeutic potential in neurodegeneration, Cardiovascular Disease, fibrosis, and metabolic disorders. However, PARPi resistance arises through restoration of DNA repair, replication fork protection, epigenetic changes, and drug-target dynamics, while adverse events-including hematologic toxicity, gastrointestinal disturbance, and organ-specific effects-limit a broader use. Next-generation PARPi with improved isoform selectivity, PROteolysis-TArgeting Chimera (PROTAC) degraders, and rational combinations with ATR/Chk1 inhibitors, immune checkpoint blockade, or epigenetic modulators offer strategies to enhance efficacy and overcome resistance. Emerging biomarker-driven approaches, including liquid biopsies and functional assays, may further personalize therapy. By integrating canonical DNA repair roles with non-canonical signaling and host-virus interactions, PARPs represent pivotal regulators. Similarly, the versatile therapeutics of PARPi have implications that extend beyond oncology into a broader and diverse range of Other human diseases.

Keywords

Cancer; Clinical applications; PARPi; PARPs; Virus.

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