Targeting MARylation and DePARylation in Cancer Therapy: New Promising Therapeutic Opportunities

The poly(ADP-ribose) polymerase (PARP) family constitutes a major group of proteins and enzymes essential for the maintenance of cellular homeostasis under physiological conditions and plays a pivotal role in the onset and progression of multiple pathological states. Members of the PARP family are classified into distinct subgroups based on their subcellular localization, structural organization, and ADP-ribosyltransferase activity. To date, the majority of studies have focused on DNA-dependent PARPs, owing to their well-established involvement in DNA repair mechanisms, cell cycle regulation, and diverse human pathologies. Nevertheless, over the past decade, a smaller subset of PARPs-limited in both abundance and enzymatic activity-has emerged as a critical regulator of numerous cellular processes, including embryonic development and disease progression. Within this subset, mono(ADP-ribosyl) transferases (MARTs) have gained growing attention as potential therapeutic targets in cancer, cardiovascular disorders, and neurodegenerative diseases. The ADP-ribose (ADPr) cycle, which comprises both branched poly(ADP-ribose) (PAR) polymers and mono-ADP-ribose moieties present either in free form or covalently bound to cellular substrates, is tightly regulated to ensure cellular homeostasis. This regulation relies on a finely tuned balance between ADP-ribosylation, DePARylation, and the subsequent recycling of mono-ADP-ribose. In this review, we provide a comprehensive overview of the biological roles of mono-ADP-ribosylation (MARylation) and DePARylation, with particular emphasis on their contribution to cancer-related processes. In addition, we discuss emerging evidence supporting their translational relevance and therapeutic potential. In conclusion, MARylation and DePARylation represent two increasingly recognized regulatory pathways whose expanding clinical significance highlights the need for deeper mechanistic understanding and further exploration in both basic and translational research.