Search Results (835)

Peritoneal carcinomatosis (PC) is a late-stage manifestation of abdominopelvic malignancies with poor prognosis and limited treatment options. Unique biochemical mechanisms within the peritoneal cavity play a key role in disease progression and resistance to therapy. Despite current therapies like systemic chemotherapy and cytoreductive surgery, patients frequently develop severe complications, including bowel obstruction, nutritional decline, and ascites, driving the need to address the pro-tumorigenic niche in the peritoneal cavity. The immune microenvironment in PC is marked by elevated proinflammatory mediators, such as IL-6 and IL-8, which skew the response toward innate rather than adaptive immune responses. IL-8 signaling, through its receptors CXCR1 and CXCR2, promotes neutrophil recruitment, chronic inflammation, angiogenesis, epithelial–mesenchymal transition, and immune evasion, making the IL-8/CXCR1/CXCR2 axis a potential therapeutic target in PC. Pre-clinical models provide evidence that IL-8 or CXCR1/CXCR2 blockade may be a valuable therapeutic strategy. IL-8 targeting agents such as monoclonal antibodies (BMS-986253) and small-molecule inhibitors (SX-682, AZD5069, navarixin) have shown efficacy in mitigating tumor growth and improving the efficacy of immune checkpoint inhibitors. Phase I and II trials have demonstrated encouraging safety profiles and preliminary efficacy when treating multiple abdominopelvic malignancies. In this review, we discuss the influence of the IL-8/CXCR1/CXCR2 axis within the peritoneal immune environment in PC and highlight recent work using IL-8 or CXCR1/CXCR2 blockade as a therapeutic strategy for PC. Continued research into the peritoneal immune microenvironment and the development of targeted therapies are essential for improving the management and prognosis of PC, potentially enhancing antitumor immunity and patient outcomes. Full article

Diabetic neuropathy (DN) is one of the most prevalent complications of diabetes mellitus, affecting a substantial proportion of patients and contributing to progressive sensorimotor dysfunction. Despite its clinical significance, available treatments are often insufficient and associated with undesirable effects. This study aims to evaluate the potential of Morus alba (MA), Angelica archangelica (AA), Valeriana officinalis (VO), and Passiflora incarnata (PI) extracts in ameliorating nociceptive alterations and inflammatory markers in the alloxan-induced diabetic rat model. Male Wistar rats with alloxan-induced DN received oral administration of the plant extracts (200 mg/kg/day) or gabapentin (100 mg/kg/day) for 15 days, the dosage regimen being established based on prior efficacy data in preclinical neuropathy models. Behavioral assessments of thermal and mechanical hypersensitivity were conducted using hot plate, tail withdrawal, von Frey, and Randall–Sellito tests. Tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) levels were quantified in brain and liver homogenates to evaluate neuro-inflammatory responses. All plant extracts produced significant improvements in nociceptive thresholds compared to diabetic control, with the most marked effects observed for MA extract. Pro-inflammatory cytokine levels were significantly reduced in all treatment groups, with MA and AA extracts inducing the most significant reductions in TNF-α and IL-6 concentrations. Computational target prediction and molecular docking analyses revealed that key phytochemicals from the plant extracts may exert antihyperalgesic effects through multi-target modulation, notably via interactions with AAK1, a kinase involved in neuropathic pain signaling. The investigated plant extracts displayed significant antihyperalgesic and anti-inflammatory activities in a rat model of DN. Among them, MA extract revealed the most consistent therapeutic profile, supporting its potential role as a strategy for managing DN. Full article

Esophageal squamous cell carcinoma (ESCC) accounts for the majority of esophageal cancers worldwide, with a poor prognosis and increasing resistance to conventional treatments. Faced with these limitations, nanoparticles (NPs) are attracting growing interest as innovative therapeutic agents capable of improving specificity and efficacy and reducing systemic toxicity. This study critically examines the pharmacological effects, mechanisms of action, and toxicity profiles of different metallic or organic nanoparticles tested on ESCC cell lines. Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) 2020 guidelines were followed by a meticulous literature search of Google Scholar, Web of Science, PubMed/Medline, and Scopus databases to achieve this goal. The results show that the anti-tumor properties vary according to the type of nanoparticle (copper(II) oxide (CuO), silver (Ag), gold (Au), nickel(II) oxide (NiO), nano-curcumin, etc.), the synthesis method (chemical vs. green), and the biological activity assessment method (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), Bromodeoxyuridine (BrdU), Cell Counting Kit-8 (CCK8) assays, etc.). NPs derived from green synthesis, such as those based on Moringa oleifera, Photinia glabra, or pomegranate bark, exhibit moderate cytotoxic activity (50% inhibitory concentration (IC₅₀) between 92 and 500 µg/mL) but show good tolerance on normal cells. In contrast, chemically synthesized NPs, such as Cu(II) complexes with 1,3,5-benzenetricarboxylic acid (H₃btc) or 1,2,4-triazole (Htrz), show lower IC₅₀ (34–86 µM), indicating more marked cytotoxicity towards cancer cells, although data on their toxicity are sometimes lacking. In addition, multifunctional nanoparticles, such as gold-based nano-conjugates targeting Cluster of Differentiation 271 (CD271) or systems combined with doxorubicin, show remarkable activity with IC₅₀ below 3 µM and enhanced tumor selectivity, positioning them among the most promising candidates for future clinical application against ESCC. The most frequently observed mechanisms of action include induction of apoptosis (↑caspases, ↑p53, ↓Bcl-2), oxidative stress, and inhibition of proliferation. In conclusion, this work identifies several promising nanoparticles (silver nanoparticles derived from Photinia glabra (PG), gold-based nano-immunoconjugates targeting CD271, and silver–doxorubicin complexes) for future pharmaceutical exploitation against ESCC. However, major limitations remain, such as the lack of methodological standardization, insufficient in vivo and clinical studies, and poor industrial transposability. Future prospects include the development of multifunctional nanocomposites, the integration of biomarkers for personalized targeting, and long-term toxicological assessment. Full article

Digital twin is a mathematical model that virtually represents a physical object or process and predicts its behavior at future time points. These simulation models enable a deeper understanding of tumorigenic processes and improve biomarker discovery in cancer research. Tumor microenvironment is marked by dysregulated signaling pathways, where kinases and phosphatases serve as critical regulators and promising sources for biomarker discovery. These enzymes operate within multiscale and context-dependent processes where spatial and temporal coordination determine cellular outcomes. Digital Twin technology provides a platform for multimodal and multiscale modeling of kinase and phosphatase processes at the patient-specific level. These models have the potential to transform biomarker validation processes, enhance the prediction of therapeutic responses, and support precision decision-making. In this review, we present the major alterations affecting kinases and phosphatase functions within the tumor microenvironment and their clinical relevance as biomarkers, and we address how digital twins in oncology can augment and refine each stage of the biomarker discovery pipeline. Introducing this emerging technology for cancer biomarker discovery will assist in accelerating its adoption and translation into precision diagnostics and targeted therapies. Full article

Background and Objectives: Methamphetamine (METH) is a potent psychostimulant known to induce neurotoxicity and neurodegeneration, leading to cognitive impairment. This study aimed to explore cubebin’s potential neuroprotective effects against METH-induced cognitive deficits by investigating its ability to suppress lipid peroxidation and pro-inflammatory markers and modulate neurotransmitter levels. Material and Methods: A total of 30 rats were taken and randomly grouped into five groups: group I—control; group II—METH 100 mg/kg/i.p.; group III—METH + cubebin (10 mg/kg/p.o.); group IV—METH + cubebin (20 mg/kg/p.o.); and group V—cubebin per os at 20 mg/kg. After a 14-day oral regimen, behavioral activities were assessed utilizing the Morris water maze (MWM). Biochemical analysis included neurotransmitters, including dopamine (DA), norepinephrine (NE), and gamma-aminobutyric acid (GABA); oxidative stress markers (malondialdehyde (MDA); nitric oxide (NO), catalase (CAT), reduced glutathione (GSH)); inflammatory cytokines [interleukin (IL-1β), IL-6, tumor necrosis factor-α (TNF-α), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)]; neurotrophic factors (BDNF, CREB); and apoptotic markers (caspase-3 and caspase-9). Furthermore, molecular docking and simulation studies were conducted. Results: Treatment with cubebin led to a marked reduction in latency during the MWM task. It significantly modulated the oxidative stress markers (SOD, GSH, CAT, MDA, and NO), inflammatory cytokines (IL-6, IL-1β, TNF-α), neurotrophic factors (CREB, BDNF), apoptotic markers (NFkB, caspase-3, caspase-9), and neurotransmitters (NE, DA, and GABA) in METH-induced memory-impaired rats. The results of molecular dynamics simulation (MDS) provided insight into the mechanisms that associate proteins CREB, BDNF, and caspase-3 in conformational dynamics upon binding to cubebin. Conclusions: In conclusion, cubebin administration improved cognitive function in rats by modulating antioxidant enzyme activity, reducing pro-inflammatory cytokines, and regulating neurotransmitter levels, demonstrating its potential neuroprotective effects against MA-induced neurodegeneration. Full article

p53 protein is a nuclear phosphoprotein that is a critical tumor suppressor, playing a key role in regulating the cell cycle and initiating apoptosis in response to DNA damage. As a transcription factor, it also activates genes involved in DNA repair and cell cycle arrest. H2AX is a histone H2A variant, which is vital for detecting DNA double-strand breaks. When phosphorylated at Serine 139, it forms γH2AX, which recruits DNA repair proteins to damage sites. The interaction between p53 and γH2AX is central to the DNA damage response, where p53 activates repair pathways and γH2AX flags the DNA lesions. It is known that impairing γH2AX while preserving p53 activity may slow cancer progression. Towards understanding this, graphene quantum dots (GQDs) offer a promising solution for tracking γH2AX and analyzing DNA damage, where they can help visualize it by investigating how p53 contributes to DNA repair at sites marked by γH2AX. This study examines the interactions between γH2AX and p53 with three different-sized two-layered GQDs (2 × 3 nm, 5 × 6 nm, and 8 × 9 nm) using the Molecular Dynamics (MD) approach. Our analysis revealed that both proteins adsorbed strongly to the 5 × 6 nm and 8 × 9 nm GQDs, with 5 × 6 nm GQD having the highest stability, making it a key candidate for future biosensing and cancer research, whereas the 8 × 9 nm GQD has the greatest potential to denature the proteins. Full article

High-risk (HR) neuroblastoma (NBL) patients often receive standardized treatment despite wide variations in clinical outcomes, underscoring the need for improved stratification tools. A distinguishing feature of NBL is the patient-specific expression of gangliosides (GGs), particularly GD2, which may serve as biomarkers. We analyzed GG profiles in 18 patient-derived tumors and 11 NBL cell lines using thin-layer chromatography and mass spectrometry. Expression of 0-, a-, and b-series GGs was examined and correlated with clinical risk, outcome, and gene expression data. Low-risk (LR) tumors expressed higher levels of complex b-series GGs. In HR tumors, five GG profiles (A–E) were identified. Profile A featured complex b-series GGs; B showed GD2 dominance; C showed synthesis arrest at GM3 or GD3 due to low expression of the GM2/GD2 synthase, encoded by the B4GALNT1 gene; D included complex a- and b-series GGs; and E was marked by GM2 and GD1a prevalence. B4GALNT1 expression served as a prognostic marker. Relapsed tumors following anti-GD2 therapy typically exhibited reduced GD2 levels, except for one profile A tumor that displayed a ceramide anchor shorter than those found in LR tumors. Astonishingly, the ceramide anchor composition of GD2 itself appears to separate LR and HR NBL, hinting at a role of ceramide synthases in NBL biology. All cell lines expressed GM2, but exhibited very low levels of complex b-series GGs. Profile C was found only in cell lines of the mesenchymal subtype. These findings support further investigation of GG composition and associated enzyme expression as potential biomarkers for risk stratification and treatment response in NBL. Full article

Drug resistance remains a major obstacle in cancer treatment despite advances in therapeutic regimens. To address this, we explored the potential of Doxorubicin (Dox) delivery in poly (lactide-co-glycolic acid) (PLGA) nanoparticles to enhance Diffuse large B-cell lymphoma (DLBCL) cell death. This research investigates the potential of Doxorubicin and advanced delivery methods. We used PLGA nanoparticles with Oleyl cysteineamide (OCA); its amphiphilic nature enables interfacial anchoring and thiol surface functionalization of PLGA NPs. Compared to PLGA-NPs, PLGA-OCA-NPs enhance immunity and induce tumor cell death. They also show significant apoptotic cell death and induced immune responses in DLBCL mouse models. Dox-conjugated PLGA-OCA-NPs (DOX-OCA) exhibit significant in vitro and in vivo anticancer activity compared to free DOX, showing remarkable antitumor effects with reduced systemic toxicity in mouse models. Our findings underscore the promising potential of PLGA-OCA-NPs in DLBCL treatment, offering a hopeful future in cancer therapy. This innovative delivery system offers enhanced immune responses and effectively addresses toxicity concerns, marking a significant step forward in cancer therapy. Full article

Background: The normal pattern of nipple enhancement on magnetic resonance imaging (MRI) is defined based on healthy individuals, as it correlates with the structural anatomy of the nipple–areola complex (NAC). Understanding the normal range of nipple morphology and enhancement on MRI allows radiologists to better identify abnormalities. Some authors have previously detailed the morphology and characteristics of nipple–areola complex enhancement, both in normal and pathologically infiltrating conditions. Our aim is to present a case series involving a population of women with breast cancer infiltrating the NAC, retrospectively evaluated at our institution. Furthermore, based on previously published literature and our own experience, we intend to propose potential standardized language to describe tumor-infiltrating NAC enhancement on MRI and compare it with CT and PET findings. Methods: Our study included 110 breast cancer patients with NAC infiltration, who were referred to our hospital from August 2023 to July 2024. All patients were candidates for neoadjuvant chemotherapy and therefore underwent MRI and CT; 33 of them also underwent PET/CT. We distinguished the MRI enhancement pattern based on morphology and intensity. There were three types of morphology: SLE (superficial linear enhancement) at the skin level, NEZ (non-enhancing area immediately below the SLE), and INE (nipple enhancement below the NEZ but above the nipple base). In INE, the pattern could be linear or patchy. Depending on the intensity, the enhancement could be minimal, mild, moderate, or marked. The enhancement on CT depended on the distribution of pathological tissue in the infiltrated NAC and could be present or absent; it could involve the nipple base, the nipple body, or both. For quantitative analysis, we used the maximum standardized uptake value (SUV) measured in early-stage PET/CT images, obtained by delineating a three-dimensional volume of interest (VOI) on the NAC. Results: In our population, the most represented enhancement pattern was INE (110), while slightly less than half of the patients showed invasion of the NEZ (49). Approximately one quarter of the patients presented linear ductal INE (36), while the majority presented patchy INE (74). On CT and PET/CT, NAC enhancement was detectable in almost all patients (102), mainly involving the base and the body together. Correlation analysis in the following pairs of variables showed a high association, with a Kendall’s tau value greater than 0.7 (p < 0.001): (1) involvement of the NEZ on ce-MR and pattern of nipple involvement on ce-CT (CT score); (2) morphological pattern of INE on ce-MR (INE score) and intensity of INE enhancement on MR; and (3) pattern of nipple involvement on ce-CT (CT score) and intensity of INE enhancement on MR. The calculated mean SUV of pathological NACs on PET/CT for early-stage images was 3.59, while the mean SUV of contralateral normal NACs was 2.12. The calculated mean NAC-SUV ratio was 1.7. Conclusions: Although pathological involvement of the NAC cannot always be assessed in the final surgical specimen due to the effects of neoadjuvant chemotherapy, so the “gold standard” of histological reference is missing, MRI and CT with morphology and enhancement descriptors, and additionally PET/CT with SUV measurement can, in our opinion, provide valuable information on the infiltrated nipple. Standardized language for describing breast tumors infiltrating the NAC is desirable to ensure consistent interpretation across different radiologists. Full article

Background: Vulvar leiomyosarcoma (VLMS) is a rare and aggressive soft tissue malignancy arising from smooth muscle cells, comprising less than 3% of vulvar cancers. Its clinical resemblance to benign vulvar lesions often leads to delayed diagnosis. Despite surgical resection and adjuvant therapy, VLMS is associated with high recurrence rates and a poor prognosis, and due to its rarity, there is no standardized management or surveillance protocol. Case Report: We present a case of high-grade VLMS in a postmenopausal woman, initially diagnosed in 2020 and managed with surgical excision and adjuvant radiotherapy. The primary tumor was a 10 cm solid, lobulated mass involving the mons pubis, with histology confirming high-grade leiomyosarcoma based on marked cellular atypia, high mitotic activity, and smooth muscle differentiation. Immunohistochemistry was positive for SMA, vimentin, and CD34, and negative for S100 and MyoD1. Five years later, the patient developed a local recurrence with an enlarged inguinal lymph node. She underwent complete tumor resection and bilateral inguinal lymphadenectomy. Histology of the recurrent lesion mirrored the initial findings, with no lymph node metastases. This case highlights the aggressive nature and potential for late recurrence in vulvar leiomyosarcoma, underscoring the importance of long-term surveillance. Conclusions: High-grade VLMS is a rare malignancy with a high recurrence risk. This case highlights the importance of early diagnosis, radical surgical treatment, and long-term surveillance. Although recurrence occurred five years after the initial treatment, timely surgical intervention led to a favorable postoperative course. Multidisciplinary management and individualized follow-up strategies remain key to improving outcomes in these rare gynecologic sarcomas. Full article

Lidocaine exhibited anti-inflammatory and immunomodulatory properties. This study aimed to investigate the anti-inflammatory effects of the lidocaine-derived analogs, EI137 and EI341, in a Staphylococcal enterotoxin B (SEB)-induced chronic rhinosinusitis (CRS). A CRS model was established using BALB/c mice via intranasal instillation of SEB. EI137 and EI341 were administered intranasally at 0.5 μg/g and 5 μg/g, respectively. Nasal symptoms and interleukin (IL)-4, IL-10, interferon (IFN)-γ, and tumor necrosis factor (TNF)-α levels in the nasal lavage fluid (NLF) were assessed. The reverse-transcription polymerase chain reaction was used to identify IFN-γ, IL-4, IL-10, and their transcription factors in the sinonasal mucosa. Histological changes were performed to assess inflammatory cell infiltration, epithelial thickness, and mucus-producing cells. SEB induced significant increases in IL-4, IL-10, and TNF-α levels in NLF and sinonasal mucosa, along with marked inflammatory cell infiltration. Intranasal EI137 and EI341 administration significantly reduced Th2 cytokine and its transcription factor, inflammatory cell infiltration, and mucus-producing cell numbers in the sinonasal mucosa. Further, EI137 suppressed Th1 cytokines, whereas EI341 enhanced Th1 responses. Both compounds promoted regulatory T cell responses, as evidenced by increased IL-10 and Foxp3 mRNA expression. EI137 and EI341 demonstrated potent local anti-inflammatory effects in a SEB-induced CRS model by modulating Th2 and Treg responses. EI137 suppressed Th1 inflammation, whereas EI341 enhanced it. These results indicate that EI137 and EI341 are promising topical agents for Th2-dominant inflammatory diseases, with distinct effects on Th1 immune responses. Full article

Upon transferal from plastic to Matrigel, melanoma cells demonstrate growth in three dimensions and form de novo vascular networks—known as vasculogenic mimicry—that are characteristic of the stemness phenotype of aggressive tumors. It has been reported that during malignant transformation, stress, or differentiation, the long-range inter-chromosomal interactions between numerous developmental genes and nucleoli are changed. The aim of this work was to study the potential mechanisms behind the development of the vasculogenic mimicry phenotype in melanoma cells and whether the formation of these 3D structures is connected with the reorganization of inter-chromosomal contacts of rDNA clusters. Here, we show that after 15 h of growth on Matrigel, and following the formation of the vasculogenic mimicry phenotype, dramatic changes occur in Mel Z cells in rDNA contacts with different genomic regions that possess mainly developmental genes. Approximately 400 genes that retained stable contacts with nucleoli were co-expressed with different lincRNAs and were highly associated with H3K27me3 marks and simultaneously regulated by different transcription factors. These genes are involved in development and cell adhesion and may control the basic stage of differentiation. The genes that acquired or increased contacts with rDNA clusters during growth on Matrigel are associated with cell morphogenesis, cell junctions, and the cytoskeleton. Here, we present the first evidence that nucleoli may be involved in both the activation and repression of particular groups of developmental rDNA-contacting genes in melanoma cells forming the vasculogenic mimicry phenotype. We conclude that the inter-chromosomal interactions between developmental genes and rDNA clusters are dynamic, and that nucleoli play an important role in the development of vasculogenic mimicry and stemness phenotypes in aggressive tumor genes. Full article

Background and Aims: Triple-negative breast cancer (TNBC) is a clinically aggressive malignancy marked by rapid disease progression, limited therapeutic avenues, and high recurrence risk. Ferroptosis an iron-dependent, lipid peroxidation-driven form of regulated cell death that has emerged as a promising therapeutic vulnerability in oncology. This study delineates the ferroptosis-associated molecular architecture of TNBC to identify key regulatory genes with prognostic and translational significance. Methods: Transcriptomic profiles from the GSE103091 dataset (130 TNBC and 30 normal breast tissue samples) were analyzed to identify ferroptosis-related differentially expressed genes (DEGs) using GEO2R. Protein–protein interaction (PPI) networks were constructed via STRING and GeneMANIA, with functional enrichment performed through Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Reactome analyses. Prognostic relevance was evaluated using GEPIA, BC-GenExMiner, and Kaplan–Meier Plotter survival analyses. Results: Six ferroptosis drivers (MAPK1, TLR4, IFNG, ATM, ULK2, and ATF3) and five suppressors (NFS1, GCLC, TP63, CD44, and SRC) were identified alongside HMOX1, a bifunctional regulator with context-dependent pro- and anti-ferroptotic activity. Enrichment analyses revealed significant associations with oxidative stress regulation, autophagy, immune modulation, and tumor progression pathways. Elevated IFNG expression was consistently linked to improve overall, disease-free, and distant metastasis-free survival, underscoring its dual function in antitumor immunity and ferroptosis sensitization. Conclusions: Ferroptosis represents a critical axis in TNBC pathophysiology, with IFNG emerging as both a prognostic biomarker and a viable therapeutic target. These insights provide a mechanistic foundation for integrating ferroptosis-inducing agents with immunotherapeutic modalities to enhance clinical outcomes and overcome therapeutic resistance in TNBC. Full article

Breast cancer (BC) remains one of the most prevalent and life-threatening malignancies worldwide, marked by significant heterogeneity and complex mechanisms of progression. Despite major advances in understanding its molecular and cellular basis, the processes driving tumor progression and metastasis continue to challenge effective treatment. Among the emerging research areas, extracellular vesicles (EVs) have gained considerable attention for their key role in intercellular communication and their contribution to cancer biology. In BC, tumor cell-derived EVs are implicated in multiple processes that promote disease progression, including tumor growth, remodeling of the tumor microenvironment, and facilitation of metastasis. By transferring oncogenic signals to recipient cells, EVs critically shape the metastatic niche and support the spread of cancer cells to distant organs. Recent studies highlight the diverse functions of BC-derived EVs in modulating immune responses, inducing angiogenesis, and enhancing cancer cell invasiveness. This review explores the role of BC-derived EVs in tumor progression and metastasis. We discuss their molecular composition, mechanisms of action, and impact on the tumor microenvironment, aiming to provide insights into their role in BC pathophysiology and discuss potential clinical applications. A deeper understanding of the complex interplay between EVs and cancer progression may pave the way for innovative strategies to combat BC and improve patient outcomes. Full article

Ferroptosis is an iron-dependent form of regulated cell death marked by lipid peroxidation in polyunsaturated phospholipids. In head and neck cancer (HNC), where resistance to chemotherapy and immunotherapy is common, ferroptosis offers a mechanistically distinct strategy to overcome therapeutic failure. However, cancer cells often evade ferroptosis via activation of nuclear factor erythroid 2-related factor 2 (Nrf2), a key regulator of antioxidant and iron-regulatory genes. HNC remains therapeutically challenging due to therapy resistance driven by redox adaptation. This review highlights the ferroptosis pathway—a form of regulated necrosis driven by iron and lipid peroxidation—and its regulation by Nrf2, a master antioxidant transcription factor. We detail how Nrf2 contributes to ferroptosis evasion in HNC and summarize emerging preclinical studies targeting this axis. The review aims to synthesize molecular insights and propose therapeutic perspectives for overcoming resistance in HNC by modulating Nrf2–ferroptosis signaling. We conducted a structured narrative review of the literature using PubMed databases. Relevant studies from 2015 to 2025 focusing on ferroptosis, Nrf2 signaling, and head and neck cancer were selected based on their experimental design, novelty, and relevance to clinical resistance mechanisms. In HNC, Nrf2 mediates resistance through transcriptional upregulation of GPX4 and SLC7A11, epigenetic stabilization by PRMT4 and ALKBH5, and activation by FGF5 and platelet-derived extracellular vesicles. Epstein–Barr virus (EBV) infection also enhances Nrf2 signaling in nasopharyngeal carcinoma. More recently, loss-of-function KEAP1 mutations have been linked to persistent Nrf2 activation and upregulation of NQO1, which confer resistance to both ferroptosis and immune checkpoint therapy. Targeting NQO1 in KEAP1-deficient models restores ferroptosis and reactivates antitumor immunity. Additionally, the natural alkaloid trigonelline has shown promise in reversing Nrf2-mediated ferroptosis resistance in cisplatin-refractory tumors. Pharmacologic agents such as auranofin, fucoxanthin, carnosic acid, and disulfiram/copper complexes have demonstrated efficacy in sensitizing HNC to ferroptosis by disrupting the Nrf2 axis. This review summarizes emerging mechanisms of ferroptosis evasion and highlights therapeutic strategies targeting the Nrf2–ferroptosis network. Integrating ferroptosis inducers with immune and chemotherapeutic approaches may provide new opportunities for overcoming resistance in head and neck malignancies. Full article