Combination therapy is a promising strategy for lung adenocarcinoma (LUAD), due to the advantages of overcoming drug resistance, side effects, and tumor heterogeneity. Herein, we report a novel dual-targeting bimetallic nanozyme (MH-iRGD) consisting of nanosized manganese ferrite (MF) after encapsulating with dopamine and methacrylic anhydride to modify hyaluronic acid, followed by integrin receptor targeting peptide (HS-PEG3400-iRGD) modification for LUAD targeted therapy. Our study confirmed that MH-iRGD combined with near-infrared irradiation (NIR) possessed dramatic photothermal effects and reactive oxygen species (ROS) production and GSH depletion abilities. Importantly, MH-iRGD possessed dual-targeting capacities for LUAD cells overexpressed CD44 and αV-integrin receptors owing to hyaluronic acid coating and iRGD modification. Inhibitors of CD44 and integrins could impair the uptake of MH-iRGD in LUAD cells. Moreover, MH-iRGD + NIR displayed excellent anti-LUAD effects as a result of the production of intracellular ROS, consumption of glutathione (GSH) and mitochondrial dysfunction. Mechanistically, NIR robustly strengthened MH-iRGD-induced ferroptosis and apoptosis by down-regulating SLC7A11, GPX4, Bcl-2 levels while up-regulating Bax level. Specifically, ferroptosis and apoptosis were increased while the LUAD progression was inhibited after intravenous injection of MH-iRGD + NIR in xenograft mouse models. Taken together, our results indicate that MH-iRGD + NIR serves as a promising targeted therapy for LUAD, which broadens the applications of highly active dual-targeting bimetallic nanozymes.

Reactive oxygen species (ROS) constitutes a group of reactive molecules that play a critical role in biological processes. Varying ROS levels have been frequently observed in cancer cells and the tumor microenvironment (TME). The role of ROS displays significant complexity in cancer development and therapy. Elevated ROS levels can induce metabolic reprogramming and promote the proliferation, invasion, and metastasis of cancer cells, resulting in cancer progression. However, excessive ROS accumulation leads to the occurrence of apoptosis, pyroptosis, necroptosis, and ferroptosis in cancer cells, which restrains tumor development. In the TME, ROS frequently promotes angiogenesis and remodels the extracellular matrix (ECM) by enhancing the differentiation of cancer-associated fibroblasts (CAFs), thereby supporting tumor growth. Concurrently, high ROS levels favour immunosuppressive cells, including M2-polarized macrophages, and regulatory T cells (Tregs), while impairing the antitumor capabilities of T cells. In the aspect of cancer therapy, it is overly simplistic to merely combine chemoradiotherapy with antioxidants as a therapeutic strategy. Instead, highlighting targeted therapies that modulate ROS is essential, given their inherent complexity. Fortunately, a variety of innovative treatments have emerged, including nanodrug delivery systems (NDDS), proteolysis-targeting chimeras (PROTAC), and adoptive cell therapy (ADT), which not only exhibit synergistic effects with immune checkpoint therapy (ICT), but also enhance the antitumor capabilities of the TME. In this paper, we elucidate the mechanism of ROS production, enumerate the role of ROS in cancer development and the TME, and discuss advancements in ROS-targeted cancer therapeutics.

Dinutuximab beta has shown limited efficacy in treating high-risk neuroblastoma (NB). Combining autophagy inhibitors with immune checkpoint inhibitors (ICIs) has proven effective in many malignancies. However, the anti-tumor effects of autophagy inhibition in conjunction with anti-GD2 immunotherapy remain unknown. In this study, dinutuximab beta induces anti-proliferation and anti-EMT activity in NB cells. Dinutuximab beta also triggers autophagy in NB cells, and inhibition of the VEGFR pathway with anlotinib amplifies dinutuximab beta-induced autophagy. In addition, dinutuximab beta induces the synthesis of the chemokine CXCL9 and the infiltration of CD8+ T cells. Mechanistically, dinutuximab beta inhibits the VEGFR/AKT/mTOR and ROS/NF-κB pathways. Furthermore, autophagy inhibition by CQ enhances CXCL9 expression and anti-tumor T cell responses of single anti-GD2 therapy in vitro and in vivo. Collectively, this study suggests autophagy inhibitors may be a promising strategy for enhancing therapeutic efficacy in NB in conjunction with anti-GD2 immunotherapy.

Resistance is a major concern for colorectal cancer patients undergoing chemotherapy. Piperlongumine (PL) has been proven to effectively reverse drug resistance in several types of cancers; however, the mechanisms associated with the reversal effect and the targets of PL in cancer drug resistance are still unclear. In this research, the reversal effects and associated mechanisms of PL in 5-Fluorouracil (5-FU) resistance colorectal cancer were investigated both in vitro and in vivo. Our data revealed that PL acted as a ROS inducer via binding and inhibiting TrxR (IC50 around 10.17 μM). By inducing ROS accumulation, PL reversed resistance to 5-FU in HCT-8/5-FU cells (reversal ratio: 4.9-fold) and enhanced the therapeutic effects of 5-FU through the dephosphorylation of Akt in BALB/c athymic nude mice bearing HCT-8/5-FU tumor xenografts. As a ROS inducer, PL reversed resistance to 5-FU by directly promoting inhibition of Akt phosphorylation, and further inhibited 5-FU efflux and promoted cell apoptosis through affecting the Akt/Foxo3/NRF2/P-gp and Akt/Foxo3/NRF2/BAD signaling pathway.

During the transformation of viral hepatitis into hepatocellular carcinoma (HCC), oxidative stress levels increase significantly, leading to tissue damage and chronic inflammation. HCC is characterized by spatiotemporal heterogeneity, which influences oxidative stress patterns, with reactive oxygen species (ROS) as the primary representative molecules. ROS serve not only as critical biomarkers of cancer but also as potential therapeutic targets for HCC, given that their increased levels can either promote or inhibit disease progression. In this review, we systematically examine the temporal heterogeneity of ROS, emphasizing its role in different stages of HCC progression caused by viral hepatitis and in influencing cell fate. We further explore ROS spatial heterogeneity at three levels: cellular, organelle, and biomolecular. Next, we comprehensively review clinical applications and potential therapies designed to selectively modulate ROS on the basis of its spatiotemporal heterogeneity. Finally, we discuss potential future applications of novel therapies that target ROS spatiotemporal heterogeneity to prevent and manage HCC onset and progression. In conclusion, this review enhances understanding of ROS in the progression of viral hepatitis to HCC and offers insights into developing new therapeutic targets and strategies centered on ROS heterogeneity.

Cell death is a crucial mechanism through which cells respond to damage and stress, thereby maintaining homeostasis. Cell death pathways include both caspase-dependent and caspase-independent mechanisms, such as apoptosis, necrosis, autophagy, and ferroptosis. The recent discovery of oxeiptosis identifies a unique form of ROS-mediated, caspase-independent cell death with apoptotic-like features. This process is regulated by key molecules, including KEAP1, PGAM5, and AIFM1, and is characterized by distinct molecular and morphological features. These regulators contribute to cellular integrity by activating cytoprotective genes through Nrf2 stabilization by KEAP1 and maintaining cellular homeostasis via PGAM5-mediated AIFM1 Ser116 dephosphorylation. In this review, we discuss the broad spectrum of oxeiptosis-mediated regulation in disease pathogenesis by combating ROS-induced cellular damage. Modulating oxeiptosis helps in disease management by mitigating ROS-induced cellular damage, restoring redox balance, and preventing pathological inflammation. Additionally, we highlight modulators such as natural derivatives and lncRNAs that trigger oxeiptosis in various diseases, including vitiligo, psoriasis, and multiple cancer types. Modulating oxeiptosis presents significant clinical implications by offering novel therapeutic strategies to mitigate oxidative stress, restore cellular homeostasis, and prevent inflammation-driven diseases. This review emphasizes potential therapeutic advances for conditions characterized by aberrant ROS accumulation, offering innovative avenues for clinical intervention and treatment development.

Temoporfin is a second-generation photosensitizer used in photodynamic therapy (PDT) for the clinical treatment of head and neck cancer. However, its role in inhibiting cancer cell viability under normoxic and hypoxic conditions remains unclear. The oral squamous cell carcinoma (OSCC) cell lines, SAS and OECM-1 were cultured under normoxic or hypoxic conditions to investigate temoporfin-based PDT-induced cell death and the underlying mechanisms. Cell viability was analyzed using the MTT assay. Intracellular reactive oxygen species (ROS) levels, cell apoptosis, intracellular ROS, iron levels, lipid peroxidation, and glutathione (GSH) levels were assessed by flow cytometry. The expression of proteins related to oxidative stress, apoptosis, autophagy, and ferroptosis was verified by western blotting. Results showed that increasing the temoporfin dose, absorption time, and illumination time was positively correlated with the inhibition of oral cancer cells. Hypoxic conditions attenuated the toxicity of temoporfin in cancer cells. OECM-1 cells were more sensitive to temoporfin than SAS cells. Temoporfin-based PDT-induced ROS exhibited similar trends to oxidative stress-inducing enzymes under both normoxic and hypoxic conditions and triggered cell autophagy and ferroptosis. Administration of the ferroptosis inhibitor BRD4770 under normoxic conditions reversed temoporfin-based PDT-induced reductions in glutathione peroxidase 4 (GPx4), increasing in light chain 3-II (LC3-II) and cleaved poly (ADP-ribose) polymerase (cleaved-PARP). This study confirms that hypoxia weakens the anticancer effects of temoporfin-based PDT and that ferroptosis plays a key role in temoporfin-based PDT-mediated cancer cell inhibition.

Reactive oxygen species (ROS) play a double-edged role in gastric cancer (GC). Higher levels of ROS in tumor cells compared to normal cells facilitate tumor progression. Once ROS concentrations rise rapidly to toxic levels, they cause GC cell death, which is instead beneficial for GC treatment. Based on these functions, nano-delivery systems taking the therapeutic advantages of ROS have been widely employed in tumor therapy in recent years, overcoming the drawbacks of conventional drug delivery techniques, such as non-specific systemic effects. In this review, the precise impacts of ROS on GC have been detailed, along with ROS-based nanomedicine therapeutic schemes. These strategies mainly focused on the use of excess ROS in the tumor microenvironment for controlled drug release and a substantial enhancement of ROS concentrations for tumor killing. The challenges and opportunities for the advancement of these anticancer therapies are also emphasized.

Ultraviolet radiation is one of the environmental factors that impacts all living beings and can cause various types of damage. In this study, the effects of UV-B and UV-C radiation on the antioxidant response, reactive oxygen species levels, and potential histological and chromosomal damage were evaluated for the first time in the spider Misumenops maculissparsus at three developmental stages (juveniles J3, J4, and adults). Juveniles exhibited significant inhibition of the antioxidant enzymes superoxide dismutase, catalase, and glutathione-S-transferase under UV radiation exposure. In adults, no enzymatic activity changes were observed, but there were increases in ROS levels, particularly under UV-C exposure, and alterations in the cellular population analyzed by flow cytometry. Histological analysis revealed substantial pigment accumulation beneath the cuticle in juveniles and, to a lesser extent, in adults, which could serve as a natural barrier and antioxidant defense against UV radiation. Cytogenetic analysis determined for the first time in this species a diploid chromosome number of 2n = 23 and identified chromatin granules in UV radiation-exposed adults, suggesting UV radiation-induced chromatin damage. These multidisciplinary findings enhance our understanding of the physiological defenses that spiders employ when exposed to UV radiation at different developmental stages.

Emerging evidence links ferroptosis-mitochondrial dysregulation to depression pathogenesis through an oxidative stress-energy deficit-neuroinflammation cycle driven by iron overload. This study demonstrates that iron accumulation initiates ferroptosis via Fenton reaction-mediated lipid peroxidation, compromising neuronal membrane integrity and disabling the GPx4 antioxidant system. Concurrent mitochondrial complex I/IV dysfunction impairs ATP synthesis, creating an AMPK/mTOR signaling imbalance and calcium dyshomeostasis that synergistically impair synaptic plasticity. Bidirectional crosstalk emerges: lipid peroxidation derivatives oxidize mitochondrial cardiolipin, while mitochondrial ROS overproduction activates ACSL4 to amplify ferroptotic susceptibility, forming a self-reinforcing neurodegenerative loop. Prefrontal-hippocampal metabolomics reveal paradoxical metabolic reprogramming with glycolytic compensation suppressing mitochondrial biogenesis (via PGC-1α/TFAM downregulation), trapping neurons in bioenergetic crisis. Clinical data further show that microglial M1 polarization through cGAS-STING activation sustains neuroinflammation via IL-6/TNF-α release. We propose a "ferroptosis-mitochondrial fragmentation-metabolic maladaptation" triad as mechanistic subtyping criteria for depression. Preclinical validation shows that combinatorial therapy (iron chelators + SIRT3 agonists) rescues neuronal viability by restoring mitochondrial integrity and energy flux. This work shifts therapeutic paradigms from monoaminergic targets toward multimodal strategies addressing iron homeostasis, organelle dynamics, and metabolic vulnerability-a framework with significant implications for developing neuroprotective antidepressants.

Nitroxides are stable organic free radicals with a wide range of applications. They have found applications in chemistry, biochemistry, biophysics, molecular biology, and biomedicine as EPR/NMR imaging techniques. As spin labels and probes, they are used in electron paramagnetic resonance (EPR) spectroscopy in the study of proteins, lipids, nucleic acids, and enzymes, as well as for measuring oxygen concentration in cells and cellular organelles, as well as tissues and intracellular pH. Their unique redox properties have allowed them to be used as exogenous antioxidants. In this review, we have discussed the chemical properties of nitroxides and their antioxidant properties. Furthermore, we have considered their use as radioprotectors and protective agents in ischemia/reperfusion in vivo and in vitro. We also presented other applications of nitroxides in protecting cells and tissues from oxidative stress and in protein studies and discussed their use in EPR/MRI.

To elucidate the effect of hydroxychavicol (HC) in combination with 5-fluorouracil (5-FU) on purine metabolism and apoptosis in colorectal cancer cell lines HT-29 and DLD-1.

The viability of HT-29 and DLD-1 cells when treated with HC, (0-1,000 µmol/L) 5-FU (0-100 µmol/L) alone, and HC+5-FU for 24 and 48 h was determined. Hypoxanthine (HPX) and xanthine oxidoreductase (XOR) were evaluated, as well as reactive oxygen species (ROS) levels and mitochondrial membrane potential (MMP). The expression levels of genes including nucleoside transporters equilibrative nucleotide transport 1 and 2 (ENT1 and ENT2), the proapoptotic gene Caspase-3 (CASP3), and the anti-apoptotic gene BCL2 were analysed by quantitative polymerase chain reaction.

Both HPX and XOR levels in cells treated with HC+5-FU were significantly decreased (P<0.05) after 24 and 48 h compared to control cells. ROS levels in HT-29 and DLD-1 treated with HC+5-FU for 24 and 48 h were 26.2% and 21.4%, and 9.1% and 20.5%, respectively, significantly lower than control cells. MMP assays indicated mitochondrial depolarisation. In HT-29 cells, ENT1 and BCL2 were downregulated at 24 h, and CASP3 was upregulated at 48 h. In DLD-1 cells, ENT1 and ENT2 were downregulated, while CASP3 showed a transient decrease at 24 h.

The combination of HC + 5-FU demonstrated synergistic effects in HT-29 and DLD-1 cells, disrupting oxidative balance and purine metabolism, as reflected in reduced hypoxanthine levels, XOR activity, and ROS production. This treatment also induced mitochondrial membrane depolarisation and altered apoptosis-related gene expression, supporting its role in apoptosis induction.

This study investigated the effects of 8,12-dimethoxysanguinarine (DSG) from Eomecon chionantha Hance on the malignant biological activity of breast cancer cells. RNA-sequencing measure analysis revealed that metastasis-related genes were significantly downregulated in DSG-treated MCF-7 cells. DSG significantly inhibits the migration ability in MCF-7 cells. Molecular docking studies demonstrated significant interactions between DSG and the Fibronectin 1 (FN1) protein, with a binding energy of -8.91 kcal/mol. Additionally, FN1 messenger RNA expression was significantly upregulated in 1085 breast tumor samples compared to normal tissue in the Cancer Genome Atlas Breast Invasive Carcinoma Collection dataset. DSG also suppressed MCF-7 cell metastasis by downregulating FN1 expression. Furthermore, DSG was identified as a promising candidate based on absorption distribution metabolism excretion toxicity and drug-likeness assessments. Combination studies indicated that DSG synergized with the conventional chemotherapeutic agent doxorubicin to suppress MCF-7 cell migration, as confirmed by wound-healing and transwell assays. Collectively, these findings suggest that DSG may serve as a potential agent for inhibiting breast cancer cell metastasis by decreasing FN1 expression.

The levels of reactive oxygen species (ROS) and the extent of ensuing DNA damage significantly influence cancer initiation and progression. Of crucial importance, the aspartate protease DDI2 has been proposed to play a pivotal role in monitoring intracellular ROS levels (to trigger oxidative eustress or distress), as well as in the oxidative DNA damage repair, through redox homeostasis-determining factor Nrf1 (encoded by NFE2L1). However, the specific role of DDI2 in the multi-step process resulting in the development and progression of liver cancer remains elusive to date. In the present study, we employed the CRISPR/Cas9 gene editing system to create two nuanced lines of DDI2 knockout (i.e., DDI2-/- and DDI2insG/-) from liver cancer cells. Subsequent experiments indicate that the knockout of DDI2 leads to increased ROS levels in hepatoma cells by downregulating two major antioxidant transcription factors Nrf1 and Nrf2 (encoded by NFE2L2), exacerbating endogenous DNA damages caused by ROS and not-yet-identified factors, thereby inhibiting cell proliferation and promoting apoptosis, and ultimately hindering in vivo malignant growth of xenograft tumor cells. Conversely, the restoration of DDI2 expression reverses the accumulation of ROS and associated DNA damage caused by DDI2 knockout, eliminating the subsequent inhibitory effects of DDI2 deficiency on both in vitro and in vivo growth of liver cancer cells. Collectively, these findings demonstrate that DDI2 deficiency impedes liver tumor growth by disrupting its survival environment, suggesting that DDI2 may serve as a novel therapeutic target for anti-cancer strategies aimed at modulating ROS or DNA damage processes.

Oxidative stress due to hyperglycemia damages the functions of retinal pigment epithelial (RPE) cells and is a major risk factor for diabetic retinopathy (DR). Paeoniflorin is a monoterpenoid glycoside found in the roots of Paeonia lactiflora Pall and has been reported to have a variety of health benefits. However, the mechanisms underlying its therapeutic effects on high glucose (HG)-induced oxidative damage in RPE cells are not fully understood. In this study, we investigated the protective effect of paeoniflorin against HG-induced oxidative damage in cultured human RPE ARPE-19 cells, an in vitro model of hyperglycemia. Pretreatment with paeoniflorin markedly reduced HG-induced cytotoxicity and DNA damage. Paeoniflorin inhibited HG-induced apoptosis by suppressing activation of the caspase cascade, and this suppression was associated with the blockade of cytochrome c release to cytoplasm by maintaining mitochondrial membrane stability. In addition, paeoniflorin suppressed the HG-induced production of reactive oxygen species (ROS), increased the phosphorylation of nuclear factor erythroid 2-related factor 2 (Nrf2), a key redox regulator, and the expression of its downstream factor heme oxygenase-1 (HO-1). On the other hand, zinc protoporphyrin (ZnPP), an inhibitor of HO-1, abolished the protective effect of paeoniflorin against ROS production in HG-treated cells. Furthermore, ZnPP reversed the protective effects of paeoniflorin against HG-induced cellular damage and induced mitochondrial damage, DNA injury, and apoptosis in paeoniflorin-treated cells. These results suggest that paeoniflorin protects RPE cells from HG-mediated oxidative stress-induced cytotoxicity by activating Nrf2/HO-1 signaling and highlight the potential therapeutic use of paeoniflorin to improve the symptoms of DR.

Reactive oxygen species (ROS), a class of highly reactive molecules, are closely linked to the pathogenesis of various cancers. While ROS primarily originate from normal cellular processes, external stimuli can also contribute to their production. Cancer cells typically exhibit elevated ROS levels due to disrupted redox homeostasis, characterized by an imbalance between antioxidant and oxidant species. ROS play a dual role in cancer biology: at moderate levels, they facilitate tumor progression by regulating oncogenes and tumor suppressor genes, inducing mutations, promoting proliferation, extracellular matrix remodeling, invasion, immune modulation, and angiogenesis. However, excessive ROS levels can cause cellular damage and initiate apoptosis, necroptosis, or ferroptosis.

This review explores molecular targets involved in redox homeostasis dysregulation and examines the impact of ROS on the tumor microenvironment (TME). Literature from recent in vitro and in vivo studies was analyzed to assess how ROS modulation contributes to cancer development and therapy.

Findings indicate that ROS influence cancer progression through various pathways and cellular mechanisms. Targeting ROS synthesis or enhancing ROS accumulation in tumor cells has shown promising anticancer effects. These therapeutic strategies exhibit significant potential to impair tumor growth while also interacting with elements of the TME.

The ROS serve as both promoters and suppressors of cancer depending on their intracellular concentration. Their complex role offers valuable opportunities for targeted cancer therapies. While challenges remain in precisely modulating ROS for therapeutic benefit, they hold promise as synergistic agents alongside conventional treatments, opening new avenues in cancer management.

Two undescribed sesquiterpene lactones (1 and 2), along with two known analogs (3 and 4), were isolated from Syneilesis aconitifolia. Their structures and absolute configurations were elucidated using spectroscopic analysis, ECD calculations, and single crystal x-ray diffraction. Compound 3 exhibited the highest cytotoxic activity against 4T1 cells, with an IC50 value of 10.89 µM. In addition, compound 3 significantly induced the apoptosis of 4T1 cells at the concentration of 20 µM. Further anticancer study showed that compound 3 distinctly increased the production of intracellular reactive oxygen species.

N6-methyladenosine (m6A) plays a role in the development of tumors. However, the specific role of VIRMA, an RNA methyltransferase, in pancreatic ductal adenocarcinoma (PDAC) remains unclear. This study shows that VIRMA expression is elevated in PDAC. Increased VIRMA levels promoted PDAC growth and spread, while reducing VIRMA expression slowed these processes. VIRMA facilitated SLC43A2 mRNA degradation through an m6A-YTHDF2 pathway. The resulting decrease in SLC43A2 reduced phenylalanine absorption and oxidative stress, further driving PDAC progression. Furthermore, alcohol increased C/EBP β expression, which bound to VIRMA's promoter, enhancing its transcription. These findings suggest a connection between alcohol consumption, m6A modifications, and phenylalanine absorption in PDAC progression, offering a new approach to combat this disease.

The peroxiredoxins (PRDXs) family plays a crucial role in balancing reactive oxygen species (ROS) levels in tumor cells. However, its potential role in prognosis and therapy response of prostate cancer (PCa) remains unknown.

In this study, we utilized 2 public single-cell RNA datasets and 8 bulk-RNA datasets to investigate the clinical value of six PRDXs family members in PCa. Expression comparison, biochemical recurrence analysis, and therapy response analysis were measured. Pathway enrichments were utilized to predict the potential down-stream pathway it may involve. In vitro experiments were used to validate the function of PRDX5 in the progression of castration-resistant prostate cancer (CRPC) cell lines.

Among the PRDXs family, PRDX5 was most related to the advancement of prostate cancer. A nomogram integrating the expression of PRDX5 with clinical features was developed to better predict clinical outcomes in PCa patients compared to 30 published signatures. Immunohistochemistry was used to verify that PRDX5 expression was higher in advanced levels of PCa tissue. Gene Set Enrichment Analysis (GSEA) and pathway predictive analysis revealed that the PRDX5 related genes were mainly relevant to ROS Pathway, Mitochondria-related functions, cellular respiration, and oxidative phosphorylation. In vitro cell proliferation assays, ROS determination assay, and apoptosis assay together revealed that depletion of PRDX5 induces apoptosis via ROS accumulation in CRPC cells. Moreover, the expression of PRDX5 in CRPC cells also affects the sensitivity to the ARSI therapy.

This study offers new evidence for determining that the expression of PRDX5 is associated with advanced tumor grade, poor prognosis, and suboptimal response to multiple therapies in PCa within the PRDXs family. Last but not least, our study provides new insights into precision medicine in PCa and provides a reference for further research on PRDX5.

Colorectal cancer (CRC) is a significant global health issue with rising incidence and mortality rates. In oncology, drug repurposing has emerged as a promising therapeutic strategy in conjunction with conventional treatments. This study aimed to evaluate the potential of repurposing propranolol (PRO), a beta blocker, for the treatment of CRC cell lines (HCT-116 and HT-29), both as a monotherapy and in combination with capecitabine (CAP).

Effects of mono- and combination therapies on viability, combination index, morphology, and cell death induction of CRC cells were assessed. Transcriptome analysis of HT-29 cells was performed using RNA sequencing. Metabolite profiling was conducted, and changes in biochemical parameters were evaluated using flow cytometry and biochemical analyses.

The combination index showed that HT-29 cells were the most responsive to the combined treatment, even with PIK3CA, B-RAF (V600E), and TP53 mutations. Moreover, ferroptosis was synergistically activated in the combined group of HT-29 in comparison to control. Furthermore, we observed an increase in OXPHOS metabolites, along with elevated intracellular and mitochondrial ROS, disruption of mitochondrial membrane potential, and greater levels of malondialdehyde (MDA) in the HT-29 combined group, which are the features of ferroptosis. Furthermore, ferroptosis induction was coupled with necroptosis, as indicated by RNA-sequencing data. Combination therapy inhibited cell migration and enhanced the immune response of HT-29 cells.

These findings suggest that PRO is promising as a potential adjuvant therapy in combination with CAP for the treatment of CRC. Only HT-29 cells with the B-RAF (V600E) mutation showed promising findings in this study.

With the rise of immunotherapy, the treatment approach for non-small cell lung cancer (NSCLC) has undergone revolutionary changes. However, the prognosis for NSCLC patients has not been significantly improved due to the development of acquired drug resistance. Therefore, there is an urgent need to develop new and more effective drugs for treating NSCLC or improving tumor treatment resistance. Traditional Chinese medicine (TCM) has been gradually incorporated into the combined treatment of NSCLC. Its active components (also known as natural products) exhibit novel structures, multi-target effects, diverse pathways, minimal toxicity, and varied biological activities, which play a therapeutic role in various diseases. Thus, natural products hold great potential for future clinical applications.

Screening main traditional plants widely used in NSCLC and their derived natural products, as well as exploring the mechanisms by which these natural products act on NSCLC-particularly focusing on their applications-can provide valuable insights for the development of therapeutic drugs targeting NSCLC.

A comprehensive, computerized literature search was conducted in PubMed, Embase, Web of Science, Cochrane Library, CNKI Scholar, the American Chemical Abstracts, and Wanfang Database up to June 2024, using the following keywords: "traditional Chinese medicine", "herbal medicine", "medicinal plants", and "herbal", paired with terms such as "non-small cell lung cancer", "therapy", "natural products", and "active ingredient".

Summarizing current research findings, we discovered eleven medicinal plants containing a total of fourteen natural products. Natural products have a significant impact on tumor progression in NSCLC, including apotosis, autophagy, pyrotosis, cell-cycle arrest and metasis. Moreover, natural products can modulate the activities of various immune cells and reshape the immune microenvironment. Combined with conventional cancer treatments, natural products demonstrate promising therapeutic effects and effectively reverse drug resistance. Furthermore,the use of nano-drug delivery systems to address limitations associated with natural products.

This review summarizes eleven medicinal plants containing a total of fourteen natural products that can enhance NSCLC treatment and indicates their action mechanisms. Furthermore, we also discuss limitations of natural products and explore the use of nano-drug delivery systems to address limitations associated with natural products.

While cationic antimicrobial peptides (AMPs) are extensively studied for antitumor effects, anionic AMPs remain underexplored. Notably, no amphibian-derived anionic cathelicidins with antitumor activity have been reported. This study identifies Boma-CATH, a novel anionic cathelicidin (net charge-3) from Bombina maxima skin, which suppresses melanoma growth in mice and triggers pyroptosis-like morphological changes in A375 cells via the NLRP3/Caspase-1/GSDMD pathway. Further investigation revealed that ROS played a crucial role in promoting pyroptosis, as NAC (ROS scavenger) and Ac-YVAD-cmk (Caspase-1 inhibitor) reversed cell death and reduced LDH/IL-1β release in vitro and in vivo. GSDMD knockdown further validated its role. Additionally, Boma-CATH inhibited A375 cell proliferation, migration, and invasion, demonstrating dual antitumor mechanisms: pyroptosis induction and metastasis suppression. Importantly, Boma-CATH caused no adverse effects in mice, highlighting its therapeutic safety. These findings position Boma-CATH as a promising melanoma treatment and expand the mechanistic understanding of anionic AMPs in oncology.

STAT3 is an important protein responsible for cellular proliferation, motility, and immune tolerance and is hyperactive in colorectal cancer, instigating metastasis, cellular proliferation, migration, as well as inhibition. It helps in proliferation of myeloid-derived suppressor cells (MDSCs), which within the tumor microenvironment (TME) suppress T cells to encourage tumor growth, metastasis, and resistance to immunotherapy, besides playing dynamic role in regulating macrophages within the tumor. Thus, MDSC is a potential target to augment immune surveillance within the TME. Herein, we report targeting both colorectal cancer and MDSCs using a glucocorticoid receptor (GR)-targeted nanoliposomal formulation carrying GR-ligand, dexamethasone (Dex), and a STAT3 inhibitor, niclosamide (N). Our main objective was to selectively inhibit STAT3, the key immunomodulatory factor in most TME-associated cells including MDSCs, and also repurpose the use of this antihelminthic, low-cost drug N for cancer treatment. The resultant formulation D1XN exhibited better tumor regression and survivability compared to GR nontargeted formulation. Further, bone marrow cell-derived MDSCs were engineered by D1XN treatment ex vivo and were inoculated back to tumor-bearing mice. Significant tumor growth inhibition with enhanced antiproliferative immune cell signatures, such as T cell infiltration, decrease in Treg cells, and increased M1/M2 macrophage ratio within the TME were observed. This reveals the effectiveness of engineered MDSCs to modulate tumor surveillance besides reversing the aggressiveness of the tumor. Therefore, D1XN and D1XN-mediated engineered MDSCs alone or in combination can be considered as potent selective chemo-immunotherapeutic nanoliposomal agent(s) against colorectal cancer.

Lithium has been identified more than six decades ago as a preferred treatment option for manic depression. Due to its affordability, stability, minimal side effects, and immunomodulatory effects, recent studies on lithium have focused on its potential anticancer properties and possible mechanisms of action. Lung cancer ranks the highest as the main cause of death in males and has high mortality rates with low survival rates. In this study, lung adenocarcinoma (A549) cells were treated with various concentrations of lithium chloride to evaluate its inflammatory and anticancer properties. The in vitro cytotoxic effects of lithium chloride were assessed using the MTT [3-(4, 5-dimethythiazol-2-yl)-2, 5-diphenyltetrazolium bromide] assay, Muse® cell death, and cell cycle analysis. The nitric oxide and oxidative stress flow cytometry Muse® assays were used to monitor inflammation profiles of lithium-treated lung adenocarcinoma cells. The MTT viability assay showed the safe use of LiCl on the noncancerous RAW 264.7 macrophage cells below a concentration of 40 mM. Lithium reduced cell viability, induced late apoptotic cell death, and disrupted normal cell cycle progression in a dose-dependent manner, leading to cell cycle arrest in the S and G2/M phases of A549 cells. The induction of cell death by lithium in A549 cells is accompanied by increased ROS and nitric oxide production. This study shows that lithium chloride possesses some immunomodulatory cytotoxic effects on A549 lung cancer cells and can be further investigated for use in lung cancer treatment.

Background/Objectives: [6]-Gingerol ([6]-G), a bioactive compound derived from Zingiber officinale (ginger), exhibits strong anticancer potential but is hindered by poor aqueous solubility and low bioavailability. This study aimed to develop and evaluate PEGylated liposomal [6]-G (6-G-Lip) to enhance its stability, bioavailability, and chemopreventive efficacy in benzo[a]pyrene (BaP)-induced lung carcinogenesis. Methods: 6-G-Lip was synthesized using a modified thin-film hydration technique and characterized for size, polydispersity index (PDI), zeta potential, encapsulation efficiency (EE%), and release kinetics. The chemopreventive effects were assessed in BaP-induced lung cancer in Swiss albino mice, with prophylactic 6-G-Lip administration from two weeks before BaP exposure through 21 weeks. Cancer biomarkers, antioxidant enzyme activity, reactive oxygen species (ROS) generation, induction of apoptosis, and histopathological alterations were analyzed. Results: 6-G-Lip exhibited a particle size of 129.7 nm, a polydispersity index (PDI) of 0.16, a zeta potential of -18.2 mV, and an encapsulation efficiency (EE%) of 91%, ensuring stability and effective drug loading. The formulation exhibited a controlled release profile, with 26.5% and 47.5% of [6]-G released in PBS and serum, respectively, at 72 h. 6-G-Lip significantly lowered cancer biomarkers, restored antioxidant defenses (SOD: 5.60 U/min/mg protein; CAT: 166.66 μm H2O2/min/mg protein), reduced lipid peroxidation (MDA: 3.3 nm/min/mg protein), and induced apoptosis (42.2%), highlighting its chemopreventive efficacy. Conclusions: This study is the first to prepare, characterize, and evaluate PEGylated [6]-G-Lip for the chemoprevention of lung cancer. It modulates oxidative stress, restores biochemical homeostasis, and selectively induces apoptosis. These findings support 6-G-Lip as a promising nanotherapeutic strategy for cancer prevention.

Bilirubin, a metabolite of hemoglobin, was long thought to be a harmful waste product, but recent studies have found it to have antioxidant and anti-tumor effects. With the extensive research on the mechanism of malignant tumor development, the antioxidant effect of bilirubin is increasingly becoming a hotspot in anti-cancer research. At present, there are two main views on the relationship between bilirubin and cancer, namely, its pro-cancer and anti-cancer effects, and in recent years, studies on the relationship between bilirubin and cancer have not been systematically summarized, which is not conducive to the further investigation of the role of bilirubin on cancer. To understand the multifaceted role of bilirubin in tumorigenesis as well as to develop more effective and affordable antitumor therapies, this review provides an overview of the effects of bilirubin on tumors in terms of oxidative, inflammatory, and cellular signaling pathways, as well as the resulting therapeutic ideas and approaches.

Cervical cancer (CC) is the fourth leading cause of cancer-related death in women globally.While early screening has reduced mortality, tumor metastasis remains a significant concern, particularly in developing countries. Recent studies have identified cuproptosis, a copper-dependent cell death mechanism, as a potential factor in tumor progression. Long non-coding RNAs (lncRNAs) are key regulators of tumor progression. This study investigates the role of cuproptosis-related lncRNA (CRL) CNNM3-DT in CC, focusing on its impact on LIAS expression, intracellular copper levels, and tumor progression.

We analyzed the expression of lnc-CNNM3-DT and LIAS in clinical samples and CC cell lines using Real-time Polymerase Chain Reaction (RT-qPCR), Western blot, and immunohistochemistry (IHC). Functional assays, including CCK-8, wound healing, transwell invasion, and flow cytometry, were used to evaluate the effects of lnc-CNNM3-DT overexpression on cell proliferation, migration, invasion, and apoptosis. Intracellular copper ion levels were measured, and correlations between lnc-CNNM3-DT, LIAS, and clinicopathological features were analyzed.

Lnc-CNNM3-DT expression was significantly higher in paracancerous tissues and normal cervical epithelial cells compared to tumor tissues and CC cell lines. Overexpression of lnc-CNNM3-DT suppressed proliferation, migration, and invasion of HeLa and SiHa cells while enhancing apoptosis. Additionally, lnc-CNNM3-DT overexpression downregulated LIAS expression and decreased intracellular copper ion levels. Correlation analysis indicated that lnc-CNNM3-DT expression was negatively associated with tumor diameter and depth of invasion, while LIAS expression showed no significant correlation with clinicopathological features.

Our findings suggest that lnc-CNNM3-DT functions as a protective factor in CC by inhibiting tumor progression through downregulation of LIAS expression and reduction of intracellular copper levels. These results highlight lnc-CNNM3-DT as a potential biomarker and therapeutic target in CC.

The metastatic cascade is a complicated process where cancer cells travel across multiple organs distant from their primary site of onset. Despite the wide acceptance of the 'seed and soil' theory, mechanisms driving metastasis organotropism remain mystery. Using breast cancer of different subtypes as the disease model, we characterized the 'metastatic profile of cancer cells' and the 'redox status of the organ microenvironment' as the primary determinants of cancer metastasis organotropism. Mechanically, we identified a positive correlation between cancer metabolic plasticity and stemness, and proposed oxidative stress as the selection power of cancer cells succeeding the metastasis cascade. Therapeutically, we proposed the use of pro-oxidative therapeutics in ablating cancer cells taking advantages of this fragile moment during metastasis. We comprehensively reviewed current pro-oxidative strategies for treating cancers that cover the first line chemo- and radio-therapies, approaches relying on naturally existing power including magnetic field, electric field, light and sound, nanoparticle-based anti-cancer composites obtained through artificial design, as well as cold atmospheric plasma as an innovative pro-oxidative multi-modal modality. We discussed possible combinations of pro-oxidative approaches with existing therapeutics in oncology prior to the forecast of future research directions. This paper identified the fundamental mechanics driving metastasis organotropism and proposed intervention strategies accordingly. Insights provided here may offer clues for the design of innovative solutions that may open a new paradigm for cancer treatment.

Tumor cells evolve strong antioxidant capacities to counteract the abnormal high level of reactive oxygen species (ROS) in the tumor microenvironment. Glutamate-cysteine ligase catalyzing subunit (GCLC) for synthesis of antioxidant glutathione (GSH) represents the key enzyme to maintain redox homeostasis of tumor cells, however, whether its activity is regulated by posttranslational modifications, such as succinylation, remains to be clarified. Here, we demonstrate the existence of succinylation modification on GCLC by in vitro and in vivo assays. NAD-dependent deacetylase Sirtuin-2 (SIRT2) serves as the desuccinylase and catalyzes GCLC desuccinylation at sites of K38, K126, and K326. Specifically, GCLC directly interacts with SIRT2, which can be substantially enhanced upon ROS treatment. This strengthened association results in GCLC desuccinylation and activation, consequently promoting GSH synthesis and rendering cancer cells resistant to ferroptosis induction. Depletion of SIRT2 decreases total GSH level and meanwhile increases the cellular susceptibility to ferroptosis, which can mostly be rescued by introducing wild-type GCLC, but not its 3K-E mutant. We further demonstrated that histone acetyltransferase P300 serves as the succinyltransferase of GCLC, and their association is remarkably decreased after ROS treatment. Thus, SIRT2-regulated GCLC succinylation represents an essential signaling axis for cancer cells to maintain their redox balance in coping with oxidative stress-induced ferroptosis.

Necroptosis is a finely regulated programmed cell death process involving complex molecular mechanisms and signal transduction networks. Among them, receptor-interacting protein kinase 1 (RIPK1), receptor-interacting protein kinase 3 (RIPK3) and mixed lineage kinase domain-like protein are the key molecules regulating this process. In recent years, gasotransmitters such as nitric oxide, carbon monoxide and hydrogen sulfide have been suggested to play a regulatory role in necroptosis. This paper reviews the evidence that these gasotransmitters are involved in the regulation of necroptosis by influencing the production of reactive oxygen species, regulating the modification of S subunits of RIPK1 and RIPK3, regulating inflammatory mediators, and signal transduction. In addition, this review explores the potential therapeutic applications of these gasotransmitters in pathological conditions such as cardiovascular disease and ischemia-reperfusion injury. Although some studies have revealed the important role of gasotransmitters in necroptosis, the specific mechanism of action is still not fully understood. Future research is needed to further elucidate the molecular mechanisms of gasotransmitters in precisely regulating necroptosis, which will help develop new therapeutic strategies to prevent and treat related diseases.

Reactive oxygen species (ROS) play a pivotal role in maintaining tissue homeostasis, yet their overabundance can impair normal cellular functions, induce cell death, and potentially lead to neurodegenerative disorders. This study identifies Drosophila Glycoprotein 93 (Gp93) as a crucial factor that safeguards tissue homeostasis and preserves normal neuronal functions by preventing ROS-induced, JNK-dependent apoptotic cell death. Firstly, loss of Gp93 induces JNK-dependent apoptosis primarily through the induction of ROS. Secondary, neuro-specific depletion of Gp93 results in ROS-JNK-mediated neurodegeneration. Thirdly, overexpression of Gp93 effectively curtails oxidative stress and neurodegeneration caused by paraquat exposure or the aging process. Furthermore, these functions of Gp93 can be substituted by its human ortholog, HSP90B1. Lastly, depletion of HSP90B1 in cultured human cells triggers ROS production, JNK activation, and apoptosis. Thus, this study not only unveils a novel physiological function of Gp93, but also provides valuable insights for understanding the physiological and pathological functions of human HSP90B1.

Glucose metabolism reprogramming provides significant insights into the development and progression of malignant tumors. This study aims to explore the temporal-spatial evolution of the glucose metabolism in HCC using single-cell sequencing and spatial transcriptomics (ST), and validates G6PD as a potential therapeutic target for HCC.

We collected single-cell sequencing data from 7 HCC and adjacent non-cancerous tissues from the GSE149614 database, and ST data from 4 HCC tissues from the HRA000437 database. Pseudotime analysis was performed on the single-cell data, while ST data was used to analyze spatial metabolic activity. High-throughput sequencing and experiments, including wound healing, CCK-8, and transwell assays, were conducted to validate the role and regulatory mechanisms of G6PD in HCC.

Our study identified a progressive upregulation of PPP-related genes during tumorigenesis. ST analysis revealed elevated PPP metabolic scores in the central and intermediate tumor regions compared to the peripheral zones. High-throughput sequencing and experimental validation further suggested that G6PD-mediated regulation of HCC cell proliferation, migration, and invasion is likely associated with glutathione metabolism and ROS production. Finally, Cox regression analysis cofirmed G6PD as an independent prognostic factor for overall survival in HCC patients.

Our study provides novel insights into the changes in glucose metabolism in HCC from both temporal and spatial perspectives. We experimentally demonstrated that G6PD regulates proliferation, migration, and invasion in HCC and propose G6PD as a prognostic marker and therapeutic metabolic target for the HCC.

Colorectal cancer is the second most common cause of death due to growing incidence. Andrographolide (AGD) induces apoptosis in colorectal cancer cells; however, oral administration of AGD is associated with hindered aqueous solubility (3.29 ± 0.73-μg.mL-1) and bioavailability of 15.87 ± 3.84%. Therefore, in the current investigation, AGD was amalgamated with Eudragit S100 (EUS100) to engineer a molecular amorphous solid dispersion (EUSD). EUSD4, an optimized molecular solid dispersion showed ~ 5.90 and ~ 7.14-fold augmentations in solubility at pH ~ 6.8 and ~ 7.4, respectively as compared to AGD alone. The% assay and drug loading were respectively measured to be 96.01 ± 3.52% and 19.85 ± 0.65%. ATR and 1H-NMR spectroscopies confirmed that the -OH group of AGD formed an intermolecular hydrogen bond with the -C = O of EUS100. Moreover, a hallo pattern of PXRD, the disappearing of an endothermic peak in DSC, the absence of a birefringence pattern under polarized light, and disorders in the initial particle shape confirmed the amorphous state of EUSD4. In addition, a ~ 4.70- and ~ 2.94-fold enhancement in dissolution profile in simulated intestinal fluid (SIF, pH ~ 6.8) and simulated colonic fluid (SCF,pH ~ 7.4) of EUSD4 suggested amendment in the hydrophilicity, wettability properties, and dissolution rate. Furthermore, the IC50 of EUSD4 was ~ 1.42-fold higher than AGD, indicating improvement in anticancer efficacy against HT-29 cells. EUSD4 exhibited superior cytotoxicity over AGD owing to the induction of apoptotic cell death, mitochondrial membrane loss (ΔΨm), remarkable S-G2/M phase cell-cycle arrest and enhanced ROS generation in HT-29 cells. In conclusion, EUSD4 warrants further in-vivo antitumor testing under a set of stringent parameters against colorectal cancer.

Inducing programmed cell death is an efficient strategy for cancer treatments, and a deep understanding of the molecular mechanisms underlying cell death pathways is of significance for the rational design of anticancer drugs. Herein, propiolamide-mediated crosstalk between ferroptosis and apoptosis is investigated. In situ monitoring of reactive oxygen species (ROS) formation and the structural changes of propiolamide compounds is achieved by Raman spectroscopy. The molecular mechanisms of propiolamides in inducing monooxygenase-mediated ROS generation and inhibiting GPX4 activities are revealed. Furthermore, the pro-ferroptotic and pro-apoptotic roles of the propiolamides containing terminal alkynes are verified. This study provides an in situ and label-free strategy for monitoring enzyme-drug interactions and their dynamics. It is a first attempt to study the structural basis of molecular crosstalk through two important enzymes in cell death. This study paves the way for designing novel drugs that are capable of triggering a synergistic contribution of multiple cell death forms to anticancer efficacy.

The extract from aerial yam bulbils (AYB) contains various bioactive compounds, yet the mechanisms underlying its effects on APAP-induced liver injury need to be investigated further. This study sought to pursue the effects of AYB extract and the potential mechanisms involved in mitigating APAP-induced hepatotoxicity.

TIB-73 cells were pretreated with AYB extract (10, 20, and 40 μg/mL) for 24 h and treated with APAP for 24 h to induce cytotoxicity.

Analysis of apoptosis-related proteins revealed that AYB extract exerts anti-apoptotic effects and inhibiting the MAPK signaling pathways, thereby reducing apoptotic cell death. Additionally, AYB extract significantly suppressed ROS overproduction by enhancing the expression of endogenous antioxidants and reducing the endoplasmic reticulum (ER) stress in APAP-treated cells, indicating that AYB extract inhibits APAP-induced oxidative stress. AYB extract effectively preserved mitochondrial membrane potential (MMP), maintained mitochondrial function-related genes, reduced mitochondrial oxidative stress, and mitigated mitochondrial damage, thereby preserving mitochondrial integrity. Additionally, AYB extract activated the Nrf2-related signaling pathway through nuclear translocation, leading to the upregulation of downstream antioxidative target genes. Diosgenin, a compound with known antioxidant properties and hepatoprotective effects, was identified in significant quantities in the AYB extract, suggesting that it may contribute to the observed hepatoprotective effects.

Overall, these findings demonstrate that AYB extract, with its antioxidative properties, effectively protects TIB-73 cells from APAP-induced liver injury.

Adenocarcinoma of the esophagogastric junction (AEG) is a common and deadly cancer, and an in-depth investigation of its molecular mechanisms of metastasis is crucial for discovering new therapeutic targets. This study explores the role of the long non-coding RNA (lncRNA) LINC00115 in AEG metastasis and its underlying mechanisms. Through the analysis of 108 pairs of AEG cancer tissues and matched adjacent tissues, we found a significant upregulation of LINC00115 in AEG tissues, closely associated with TNM staging and lymph node metastasis. Utilizing cell counting kit-8 (CCK-8) assays, colony formation experiments, wound healing assays, flow cytometry for apoptosis and cell cycle analysis, and Transwell assays, we have confirmed that LINC00115 significantly promotes proliferation, migration, and invasion of AEG cells in vitro. Animal experiments further validate the role of LINC00115 in promoting tumor growth and metastasis in vivo. Additionally, our nuclear-cytoplasmic fractionation experiments and RNA fluorescence in situ hybridization (FISH) reveal that LINC00115, along with its interacting protein KH-Type splicing regulatory protein (KHSRP), predominantly localizes to the cell nucleus. By conducting RNA pull-down assays and mass spectrometry (MS) analysis, we have identified a direct interaction between LINC00115 and KHSRP protein and further determined their binding sites through catRAPID and ENCORI databases. This study provides evidence of LINC00115 as a novel biomarker and potential therapeutic target for AEG and offers a fresh perspective on understanding the molecular mechanisms of AEG metastasis.

Alpha-Momorcharin (α-MMC), as one of the most important type I RIPs, has been reported to exert inhibitory effects against various tumour cells through its N-glycosidase activity. The present study was designed to propose an efficient purification strategy and explored its mechanism of apoptosis signalling pathway against human liver cancer cells SK-Hep-1. α-MMC can be successfully obtained by our purification strategy combining ion-exchange and gel-filtration chromatography. The functional studies revealed that α-MMC obviously increased the level of ROS and apoptosis rate, induced cell cycle arrest in the G1 phase, and depolarised MMP of SK-Hep-1 cells. To further confirm whether α-MMC could induce mitochondria involved apoptosis, we found that PARP-1, Caspase-3, Caspase-9, and BCL-2 were downregulated upon α-MMC. Taken together, these results suggested that this natural purified α-MMC can induce apoptosis involved mitochondria and may serve as a potential novel therapeutic drug in the treatment of human liver cancer in the future.

As a prevalent industrial material and component of consumer products, bisphenol A (BPA) is linked to hormone homeostasis disruption and potential carcinogenicity. However, the precise mechanisms through which BPA contributes to thyroid carcinogenesis, especially in papillary thyroid carcinoma (PTC), are not fully understood. This study investigates how BPA boosts the proliferation and tumorigenic characteristics of thyroid cells. BPA exposure significantly increased cell proliferation in a duration-dependent manner at a concentration of 0.5 μM, which is slightly higher than human exposure levels. Therefore, this study utilized BPA treatment concentrations of 0.1 µM and 0.5 µM. BPA augmented the invasiveness of PTC cells with a dependency on both dosage and temporal factors. RNA-seq and gene expression analysis from normal human thyroid follicular epithelial cells suggested that BPA upregulated genes related to oxidative stress and thyroid cancer. Concurrently, our study revealed significant upregulation of NOX4 in thyroid tumors compared to normal thyroid tissues, with higher expression levels observed in advanced carcinomas by analyses of the TCGA database. BPA induces the upregulation of NOX4 in human thyroid cells, thereby triggering the activation of MAPK and PI3K/AKT pathways. In xenograft models, BPA treatment resulted in increased tumor size and Ki-67 proliferation index, accompanied by upregulated NOX4 expression. Additionally, BPA exposure led to higher levels of free triiodothyronine (FT3), indicating thyroid hormone disruption. Mechanistically, BPA activates the MAPK and PI3K/AKT pathways via NOX4, leading to increased ROS production and cell proliferation. This was further demonstrated through the use of ROS scavenger treatment and si-NOX4, which showed that BPA stimulates ROS generation by activating NOX4/MAPK and NOX4/PI3K/AKT pathways in thyroid cells. This finding enhances our understanding of the pathogenesis of PTC related to BPA exposure and highlights the necessity for rigorous health risk assessments regarding BPA exposure.