PARG (poly(ADP-ribose) glycohydrolase) is a dePARylating enzyme that catalyzes the hydrolysis of ribose-ribose bonds in poly(ADP-ribose) 1. It functions primarily as an exo-glycohydrolase, degrading poly(ADP-ribose) to ADP-ribose monomers while preserving mono-ADP-ribosylation on target proteins 2. Following DNA damage, PARG rapidly degrades transiently synthesized poly(ADP-ribose), preventing detrimental accumulation during replication stress 3. Beyond DNA repair, PARG participates in nuclear ATP synthesis alongside PARP1 and NMNAT1, supporting energy-demanding chr10 remodeling 4, and is required for retinoid acid-dependent gene transactivation by removing poly(ADP-ribose) from histone demethylase KDM4D 3. Clinically, PARG emerges as an oncogenic target in multiple cancer types. High PARG expression predicts poor prognosis in hepatocellular carcinoma and cholangiocarcinoma, promoting tumor growth through distinct mechanisms: HCC progression via DDB1-dependent c-Myc stabilization 5, and cholangiocarcinoma progression via Hippo pathway suppression through ITCH dePARylation 6. PARG inhibition reduces replication fork stability and induces single-stranded DNA gaps in HR-deficient ovarian cancer cells 7, showing therapeutic potential. Notably, PARG inhibitors enhance responses to chemotherapy and immunotherapy by reducing STAT3 phosphorylation, activating antitumor immune responses 856. These findings position PARG inhibitors as promising precision medicine agents for DDR-deficient and immune-suppressive cancers.