PARP1 as a Central Node in DNA Repair and Epigenetic Regulation: Implications for Biomarker Discovery and Targeted...

PARP1 is a key regulator of genome integrity, DNA repair, and epigenetic control. PARP inhibitors (PARPis), designed as nicotinamide mimetics that target the NAD⁺ binding pocket, exploit synthetic lethality in homologous recombination-deficient tumors and have been approved for the treatment of multiple cancers.

A systematic literature review (2020-2025) was conducted using major databases to evaluate structural, mechanistic, and translational aspects of PARP1, with emphasis on NSCLC.

Approved PARPis share conserved pharmacophores but differ in scaffold architecture, PARP1/2 selectivity, and trapping potency, which influence their PK/PD profiles. In NSCLC, elevated PARP1 activity is associated with poor prognosis and oncogenic signaling (EGFR/ALK), while therapeutic efficacy depends on both catalytic inhibition and trapping mechanisms.

Emerging strategies targeting PARP1 regulatory networks, including HPF1, ALC1, and PAR turnover enzymes, demonstrate therapeutic potential, although challenges related to specificity, toxicity, and drug resistance remain significant.

Key challenges include improving PARP1 selectivity, overcoming resistance (e.g., BRCA reversion), and developing next-generation agents targeting PARP1 regulatory networks such as HPF1 and PARG.