Fig. 3. Mechanism of action of PARP inhibitors. Initially, it was hypothesized that PARP inhibitors exerted their effects by inhibiting PARylation and inducing cytotoxicity. However, subsequent findings revealed that the primary mechanism underlying tumor cell death was the entrapment of the PARP1 enzyme at sites of DNA damage. When DNA damage occurs, resulting in single-strand breaks (SSBs), PARP1 plays a crucial role in their precise repair. However, when PARP1 becomes entrapped, it poses a significant threat to the progression of replication forks during the S phase of the cell cycle. Consequently, this leads to the collapse of replication forks and the generation of double-strand breaks (DSBs). In cells with intact BRCA genes, these breaks can be accurately repaired through the process of homologous recombination (HR) without introducing errors. Conversely, cells deficient in BRCA1/2 exhibit impaired HR and instead rely on error-prone DNA end-joining (EJ) pathways, such as classical non-homologous EJ or alternative EJ, to mend the DSBs arising from replication fork collapse. This process triggers the accumulation of chromosomal abnormalities and ultimately culminates in cell death through mitotic catastrophe. PARP: poly(ADP-ribose) polymerase, PARylation: poly(ADP-ribosyl) ation. Figure created with BioRender.com.