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<p>Cancer remains the second leading cause of death globally. Poly (ADP-ribose) polymerase inhibitors (PARPi) are effective targeted therapies, but their use is largely limited to <i>BRCA</i>-deficient cancers and is often hampered by resistance. This review explores combining PARPi with curcumin, a natural polyphenol, as an adjunct therapy. We reviewed literature and employed a network pharmacology approach to investigate shared molecular mechanisms. Curcumin induces DNA double-strand breaks while simultaneously impairing multiple repair pathways, including homologous recombination and non-homologous end joining. It also disrupts the ATR-CHK1 checkpoint. PARPi complements this by inhibiting base excision repair and trapping PARP-1 on DNA. This multi-pronged assault culminates in synthetic lethality and apoptosis. Our network pharmacology analysis identified 33 shared protein targets between curcumin and four FDA-approved PARPi. The resulting interaction network highlighted central hubs like ESR1 and SRC. Enriched pathways included PI3K/AKT signaling, VEGF signaling, and endocrine resistance. These findings suggest the combination targets not only DNA repair but also critical kinase signaling and tumor microenvironment pathways. This synergy offers a promising strategy to overcome resistance and expand PARPi to <i>BRCA</i>-proficient cancers. Significant challenges remain, including curcumin’s low bioavailability and the complete absence of clinical trial data. Further research is essential to translate this preclinical potential.</p> Graphical abstract <p></p>

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The golden touch: a comprehensive network pharmacology-guided review of synergy between curcumin and PARP inhibitors

  • 期刊论文

  • 发表日期：

    2025年11月24日

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  • Elina Khanehzar,
  • Fatemeh Shams,
  • Amirsajad Jafari

摘要

Cancer remains the second leading cause of death globally. Poly (ADP-ribose) polymerase inhibitors (PARPi) are effective targeted therapies, but their use is largely limited to BRCA-deficient cancers and is often hampered by resistance. This review explores combining PARPi with curcumin, a natural polyphenol, as an adjunct therapy. We reviewed literature and employed a network pharmacology approach to investigate shared molecular mechanisms. Curcumin induces DNA double-strand breaks while simultaneously impairing multiple repair pathways, including homologous recombination and non-homologous end joining. It also disrupts the ATR-CHK1 checkpoint. PARPi complements this by inhibiting base excision repair and trapping PARP-1 on DNA. This multi-pronged assault culminates in synthetic lethality and apoptosis. Our network pharmacology analysis identified 33 shared protein targets between curcumin and four FDA-approved PARPi. The resulting interaction network highlighted central hubs like ESR1 and SRC. Enriched pathways included PI3K/AKT signaling, VEGF signaling, and endocrine resistance. These findings suggest the combination targets not only DNA repair but also critical kinase signaling and tumor microenvironment pathways. This synergy offers a promising strategy to overcome resistance and expand PARPi to BRCA-proficient cancers. Significant challenges remain, including curcumin’s low bioavailability and the complete absence of clinical trial data. Further research is essential to translate this preclinical potential.

Graphical abstract