NQO1 (NAD(P)H dehydrogenase, quinone 1)

Pharmacologic inhibition of NQO1 using skullcapflavone II restores apoptotic sensitivity and enhances cisplatin efficacy, resulting in significant tumor suppression with favorable tolerability in preclinical models...Validation across seven independent cohorts, demonstrates robust performance in identifying patients at risk of progression and BCG failure. These findings establish a biologically grounded framework for precision management of T1HG bladder cancer.

RES also suppressed IL-6, IL-8, TNF-α, and nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) expression, and enhanced anti-apoptotic genes B-cell lymphoma-extra-large and B-cell lymphoma 2 expression (P < 0.05). In conclusion, RES supplementation (400 mg/kg) effectively improved laying performance, egg quality, and oxidative and inflammatory responses in laying hens, suggesting its potential as a nutritional strategy to support laying performance during the late production stages.

A murine psoriasis model was induced by 6-day continuous topical imiquimod (IMQ) application; cellular models were established by stimulating keratinocyte lines with tumor necrosis factor-alpha (TNF-α)/interleukin-17A (IL-17A)...siNrf2 abolished Nef-mediated inhibition of NF-κB/ERK phosphorylation, cytokine down-regulation and ΔΨm loss. Neferine ameliorates psoriasis by inducing oxidative stress-driven apoptosis in hyper-proliferative keratinocytes and by activating Keap1-Nrf2-mediated anti-inflammatory signaling to block the IL-23/IL-17 axis, offering a promising small-molecule strategy for psoriasis management.

Molecular docking studies and molecular dynamics simulations demonstrated that 18 exhibits a strong binding affinity and forms key stabilizing interactions within the Nrf2-binding domain of Kelch-like ECH-associated protein 1 (Keap1). These results demonstrate that quinazoline sulfonamide derivatives are promising oxidative stress modulators with tumor targeting ability.

Boldine treatment significantly attenuated biochemical and molecular alterations, enhanced dihydropyrimidine dehydrogenase expression involved in 5-FU metabolism, and ameliorated histopathological changes. Overall, these findings suggest that boldine may exert hepatoprotective effects against 5-FU-induced liver injury, potentially through modulation of oxidative stress and inflammatory pathways.

Meanwhile, treatment with irradiated P. cubeba reduced the severity of these changes by increasing anti-inflammatory cytokine IL-10 and enhancing FOXP3 expression, a key regulator of T regulatory (Treg) cells, in arthritic rats. These findings demonstrate that irradiated P. cubeba exerts immunomodulatory, antioxidant, and anti-inflammatory effects.

However, all variants exhibited markedly impaired enzyme turnover, highlighting alterations in the enzyme's substrate specificity toward quinones. The data presented here demonstrate that Tyr126 and Tyr128 optimize both substrate binding geometry as well as overall enzyme conformational dynamics during the asymmetric catalytic cycle of the NQO1 homodimer.

The most active compounds were further assessed in a cisplatin-resistant A2780 subline, with N-acetylcysteine (NAC) used to probe reactive oxygen species (ROS)-dependent mechanisms. Their cytotoxicity was abrogated by NAC, indicating a ROS-dependent mode of action. CoMFA and CoMSIA models accurately predicted the activity of synthetic chalcones, and the biological findings identify these derivatives as promising candidates for the treatment of ovarian cancer, including chemoresistant forms.

We also demonstrated that chemical inhibition of these proteins using RSL3 (GPX4 inhibitor) and erastin (xCT inhibitor) significantly suppressed osteosarcoma cell growth. Collectively, our findings reveal that GPX4 inhibition initiates ferroptosis while simultaneously activating NRF2-driven antioxidant defenses, iron homeostasis mechanisms, and adaptive cell survival signaling. The results highlight potential therapeutic strategies that combine GPX4 inhibition with targeted disruption of compensatory pathways to overcome ferroptosis resistance in osteosarcoma.

Furthermore, Dac epigenetically restores the expression of STING and GSDME via DNA demethylation, markedly augmenting cGAS-STING activation and pyroptosis. As a result, PLMD treatment enhances dendritic cell maturation and T-cell priming, ultimately achieving pronounced tumor growth inhibition and robust antitumor immune responses in a 4T1 tumor model.

Importantly, combined treatment with panobinostat and the anti-angiogenic agent anlotinib resulted in superior inhibition of tumor growth and vascularization compared with either monotherapy in patient-derived organoid xenograft models. Together, these findings uncover an enzymatic activity-independent RNA regulatory function of NQO1 in ESCC and provide a mechanistic rationale for targeting the NQO1/AGRN axis.

Accordingly, under the experimental conditions applied, exposure did not result in detectable DNA or chromosomal damage. In silico analysis indicated that the mixture's toxicity is largely driven by the AHR-CYP-NQO1 axis.