Arginine restriction exploits DNMT3B-ASS1-driven arginine auxotrophy and mTORC1-suppressed autophagy to overcome niraparib resistance in ovarian cancer.

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Acquired resistance to poly(ADP-ribose) polymerase (PARP) inhibitors limits the durability of niraparib maintenance therapy in epithelial ovarian cancer. Here, integrated multi-omic and functional analyses of paired parental and niraparib-resistant models identified DNMT3B-dependent promoter hypermethylation and silencing of argininosuccinate synthase 1 (ASS1), establishing an arginine-auxotrophic state in resistant cells. Despite impaired de novo arginine synthesis, resistant cells maintained intracellular arginine through enhanced extracellular acquisition. Arginine deprivation alone induced a largely cytostatic state characterized by mitochondrial dysfunction, oxidative stress, and energetic imbalance, whereas its combination with niraparib produced marked synergy, amplifying DNA damage, suppressing homologous recombination, and driving cell death. Mechanistically, arginine restriction depleted NAD(P)H and acetyl-CoA pools, reduced histone H3 acetylation, and compressed chromatin accessibility at DNA repair loci, thereby intensifying niraparib-induced genotoxic stress. Resistant cells also displayed persistent mTORC1 activation and blunted autophagic flux; mTORC1 inhibition restored autophagy and niraparib sensitivity but attenuated the incremental benefit of arginine deprivation, identifying mTORC1-constrained autophagy as a key determinant of this vulnerability. In vivo, a well-tolerated 50% arginine-restricted diet lowered circulating and intratumoral arginine and potentiated niraparib across resistant xenograft, patient-derived, and maintenance-mimicking models. Clinically, DNMT3B-high/ASS1-low tumors were associated with shorter progression-free survival, and serial plasma arginine declined prior to progression during niraparib maintenance, supporting plasma arginine dynamics as an exploratory candidate monitoring biomarker. Together, these findings define an epigenetically fixed arginine dependency in niraparib-resistant ovarian cancer and support partial dietary arginine restriction as a practical resensitization strategy.