IP-DNQ 与 rucaparib 联合靶向氧化还原-DNA修复，在 NQO1 阳性肿瘤中诱导氧化性 DNA 损伤及 GSDME 介导的细胞焦亡

Cancer remains a leading cause of mortality worldwide, with current therapies often failing to eradicate resistant tumor populations. This highlights the need for strategies that exploit tumor-specific metabolic and DNA repair vulnerabilities. NAD(P)H:quinone oxidoreductase 1 (NQO1), commonly overexpressed in solid tumors, enzymatically activates redox-cycling prodrugs, offering a selective tumor targeting strategy. Isopentyl-deoxynyboquinone (IP-DNQ), a potent NQO1-bioactivatable quinone, undergoes futile redox cycling to generate reactive oxygen species (ROS), induce oxidative DNA damage, and deplete NAD⁺/ATP. Given that PARP activation is an early response to DNA damage, we investigated the mechanistic synergy between NQO1-dependent redox cycling and PARP inhibition using IP-DNQ combined with rucaparib, an FDA-approved PARP inhibitor. Rucaparib significantly enhanced IP-DNQ-induced ROS accumulation, DNA strand breaks, and metabolic collapse in an NQO1-dependent manner. This combination triggered caspase-3 activation and gasdermin E (GSDME) cleavage, leading to pyroptotic cell death characterized by LDH release and IL-1beta secretion. Both pharmacologic inhibition and genetic knockout of NQO1 abolished these effects, confirming the essential role of IP-DNQ bioactivation. Importantly, the IP-DNQ/rucaparib combination suppressed tumor growth and prolonged survival in orthotopic pancreatic and lung cancer models without causing systemic toxicity. These findings uncover a novel redox-DNA repair co-targeting strategy that amplifies oxidative DNA damage and redirects apoptosis toward immunogenic GSDME-mediated pyroptosis. This approach broadens the therapeutic scope of PARP inhibitors and offers a promising platform for treating NQO1-overexpressing cancers.