Nuclear factor erythroid 2-related factor 2 (NRF2) orchestrates redox balance, metabolism, and cellular stress responses, acting as both a tumor suppressor and promoter depending on the disease stage. In advanced cancers, persistent NRF2 activation—through KEAP1/NFE2L2 mutations or oxidative adaptation—drives epithelial-to-mesenchymal transition, metabolic reprogramming, and immune evasion, promoting tumor invasion (T) and metastasis (M). Recent pharmacologic efforts seek to exploit this duality. NRF2 inhibitors such as brusatol, halofuginone, and ML385 suppress NRF2 transcriptional activity or disrupt DNA binding, reducing motility, invasion, and metastatic dissemination in preclinical models. In contrast, NRF2 activators, such as bardoxolone methyl (CDDO-Me), sulforaphane, and dimethyl fumarate, exhibit chemopreventive effects by enhancing detoxification and mitigating oxidative DNA damage during early tumorigenesis. Furthermore, metabolic interventions, such as glutaminase or G6PD inhibitors, target NRF2-driven anabolic and antioxidant pathways essential for metastatic fitness. Therefore, understanding the temporal and contextual effects of NRF2 signaling is crucial for therapeutic design. The aim of this review is to examine how pharmacological modulation of NRF2 influences the invasive and metastatic dimensions of tumor progression, in addition to discussing its potential integration into TNM-based prognostic and treatment frameworks.

Computed tomography (CT) is fundamental to modern medicine, yet ionizing radiation (IR) exposure causes DNA damage. Although often underestimated, at current doses, CT may account for ~5% of new cancer diagnoses. Complementary radioprotective approaches beyond dose reduction are needed. We conducted a prospective observational study to characterize IR-induced oxidative stress (OS)-mediated DNA damage in modern CT to explore potential antioxidant-based radioprotective strategies. In volunteers not exposed to IR (A_NONE) and in patients with two-phase abdominal–pelvis CT (B_EXPOSURE), blood samples were collected at T_BASE-min 0 and T_POST-min 60 to measure biomarkers of OS (oxidative damage and antioxidant capacity) and DNA damage. Thirty-five subjects (n = 17 A_NONE/18 B_EXPOSURE) were studied. Body mass index and DNA damage in T_BASE were comparable between groups. In A_NONE, biomarkers of OS and DNA damage did not change between T_BASE and T_POST (p > 0.05 for all). In B_EXPOSURE, DNA damage was significantly increased [15% (−15–60); p < 0.001], which was associated with consistent increased antioxidant enzyme activity [p < 0.05 for all antioxidant enzymes]. In modern CT with relatively low effective dose (ED) levels, a significant increase in DNA damage was observed along with increased antioxidant enzyme activity as defensive response and marker of OS-mediated damage-mediating mechanisms. These findings warrant interventional studies to evaluate antioxidant-based radioprotective strategies.

Human melanoma is a highly aggressive malignant tumor originating from epidermal melanocytes, characterized by intrinsic resistance to apoptosis and the reprogramming of proliferation and survival pathways during progression, leading to high morbidity and mortality rates. This malignancy displays a marked propensity for metastasis and often exhibits poor responsiveness to conventional therapies. Fatty acids, such as n-3 polyunsaturated fatty acids (PUFAs) docosahexaenoic and eicosapentaenoic acids, exert various physiological effects on melanoma, with increasing evidence highlighting the anti-tumorigenic, anti-inflammatory, and immunomodulatory properties. Additionally, n-3 PUFAs have demonstrated their ability to inhibit cancer metastatic dissemination. In the context of cancer treatment, n-3 PUFAs have been investigated in conjunction with chemotherapy as a potential strategy to mitigate severe chemotherapy-induced side effects, enhance treatment efficacy and improve safety profiles, while also enhancing the responsiveness of cancer cells to chemotherapy. Furthermore, dietary intake of n-3 PUFAs has been associated with numerous health benefits, including a decreased risk and improved prognosis in conditions such as heart disease, autoimmune disorders, depression and mood disorders, among others. However, the specific mechanisms underlying their anti-melanoma effects and outcomes remain controversial, particularly when comparing findings from in vivo or in vitro experimental studies to those from human trials. Thus, the objective of this review is to present data supporting the potential role of n-3 PUFA supplementation as a novel complementary approach in the treatment of malignant cancers such as melanoma.

Prostate cancer (PCa) is the most common malignancy in men worldwide. Multiparametric MRI (mpMRI) improves the detection of clinically significant PCa (csPCa); however, it remains limited by false-positive findings and inter-observer variability. Time-dependent diffusion (TDD) MRI provides microstructural information that may enhance csPCa characterization beyond standard mpMRI. This prospective observational diagnostic accuracy study protocol describes the evaluation of PROS-TD-AI, an in-house developed AI workflow integrating TDD-derived metrics for zone-aware csPCa risk prediction. PROS-TD-AI will be compared with PI-RADS v2.1 in routine clinical imaging using MRI-targeted prostate biopsy as the reference standard.

Prostate cancer (PCa) is the most frequently diagnosed malignancy in men and the eighth leading cause of cancer death worldwide. Multiparametric MRI (mpMRI) has become central to the diagnostic pathway for men at intermediate risk, improving detection of clinically significant PCa (csPCa) while reducing unnecessary biopsies and over-diagnosis. However, mpMRI remains limited by false positives, false negatives, and moderate to substantial interobserver agreement. Time-dependent diffusion (TDD) MRI, a novel sequence that enables tissue microstructure characterization, has shown encouraging preclinical performance in distinguishing clinically significant from insignificant PCa. Combining TDD-derived metrics with machine learning may provide robust, zone-specific risk prediction with less dependence on reader training and improved accuracy compared to current standard-of-care. This study protocol outlines the rationale and describes the prospective evaluation of a home-developed AI-enhanced TDD-MRI software (PROSTDAI) in routine diagnostic care, assessing its added value against PI-RADS v2.1 and validating results against MRI-guided prostate biopsy.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide and is characterized by a high recurrence rate, limited treatment options, and frequent resistance to systemic therapy. A key factor in this resistance is the persistent activation of nuclear factor erythroid 2-related factor 2 (NRF2), a transcription factor that normally protects against oxidative stress but, in malignant hepatocytes, suppresses ferroptosis by restricting lipid peroxidation. This dual function positions NRF2 as a key target for therapeutic modulation in HCC. Recent preclinical studies demonstrate that NRF2 maintains tumor survival by regulating antioxidant and iron management pathways, such as GPX4, SLC7A11, and ferritin, which together mitigate lipid peroxidation and prevent ferroptotic cell death. Multiple pharmacological strategies have been evaluated to counteract this effect, including direct NRF2 inhibitors such as camptothecin (CPT) and brusatol, preoperative modulators such as metformin and picropodophyllin (PPP), and natural compounds such as tiliroside, bavaquine, and arenobufagin. These interventions often show synergistic activity with sorafenib and other standard treatments, while postoperative effectors such as CYP4F11 and the NRF2-SLC7A11-GPX4 axis have emerged as promising additional intervention points. Despite compelling results in vitro and animal model results, several challenges limit its application to clinical practice. These include the lack of dedicated clinical trials, the limited specificity of available inhibitors, tumor heterogeneity, and potential safety concerns in cirrhotic livers. Future research focuses on the development of selective NRF2 modulators, hepatocyte-targeted approaches such as proteolysis-targeted chimeras (PROTACs) and GalNAc-conjugated oligonucleotides, and biomarker-based patient stratification using genomic, immunohistochemical, and transcriptomic indicators of NRF2 activation. Taken together, contextual NRF2 modulation represents a promising strategy to restore sensitivity to ferroptosis, overcome drug resistance, and improve outcomes in HCC patients.