Aging is a natural biological process that is characterized by the progressive decline in physiological functions and an increased vulnerability to age-related diseases. The aging process is driven by different cell and molecular mechanisms. It has recently been shown that aging is associated with heightened vulnerability to ferroptosis (an intracellular iron-dependent form of programmed cell death). This susceptibility arises from various factors including oxidative stress, impaired antioxidant defences, and dysregulated iron homeostasis. The progressive decline in cellular antioxidant capacity and the accumulation of damaged components contribute to the increased susceptibility of aging cells to ferroptosis. Dysregulation of key regulators involved in ferroptosis, such as glutathione peroxidase 4 (GPX4), iron regulatory proteins, and lipid metabolism enzymes, further exacerbates this vulnerability. The decline in cellular defence mechanisms against ferroptosis during aging contributes to the accumulation of damaged cells and tissues, ultimately resulting in the manifestation of age-related diseases. Understanding the intricate relevance between aging and ferroptosis holds significant potential for developing strategies to counteract the detrimental effects of aging and age-related diseases. This will subsequently act to mitigate the negative consequences of aging and improving overall health in the elderly population. This review aims to clarify the relationship between aging and ferroptosis, and explores the underlying mechanisms and implications for age-related disorders, including neurodegenerative, cardiovascular, and neoplastic diseases. We also discuss the accumulating evidence suggesting that the imbalance of redox homeostasis and perturbations in iron metabolism contribute to the age-associated vulnerability to ferroptosis.

Single-atom enzymes (SAZ) show great promise in cancer therapy, particularly chemodynamic therapy, due to their high catalytic activity. They can increase reactive oxygen species (ROS) in tumor cells, causing cell damage and death. However, glutathione (GSH) in tumors can neutralize ROS, reducing SAZ effectiveness. Lowering GSH levels can enhance the effectiveness of SAZ in killing tumor cells, and inhibiting its synthesis at the source might be a promising approach. Glutaminase (GLS1) inhibitors like BPTES can reduce GSH by disrupting glutamine metabolism. This study develops a thermosensitive hydrogel with Fe-based SAZ and BPTES. Upon infrared laser irradiation, the hydrogel releases FeSAZ and BPTES into tumor cells. FeSAZ generates ▪OH from H2O2, while BPTES reduces glutathione (GSH) synthesis in tumor cells, weakening their defenses and enhancing the cytotoxic effects of ▪OH. This combined strategy shows strong potential for effective tumor suppression. Our strategy provides new insights into cancer treatments, potentially offering a more effective therapeutic options for patients.

Redox regulators are emerging as critical mediators of lung tumorigenesis. NRF2 and its negative regulator KEAP1 are commonly mutated in human lung cancers, leading to NRF2 accumulation and constitutive expression of NRF2 target genes, many of which are at the interface between antioxidant function and anabolic processes that support cellular proliferation. Nrf2 activation promotes lung tumor initiation and early progression in murine models of lung cancer, but which Nrf2 targets mediate these phenotypes is unknown. Nrf2 regulates two parallel antioxidant systems mediated by thioredoxin reductase 1 (TXNRD1) and glutathione reductase (GSR), which promote the reduction of protein antioxidant thioredoxin (TXN) and tripeptide antioxidant glutathione (GSH), respectively. We deleted TXNRD1 and GSR alone, or in combination, in lung tumors harboring mutations in KrasG12D and Nrf2D29H. We found that tumor initiation was promoted by expression of GSR, but not TXNRD1, regardless of Nrf2 status. In contrast, Nrf2D29H tumors, but not Nrf2WT, were dependent on TXNRD1 for tumor progression, while GSR was dispensable. Simultaneous deletion of GSR and TXNRD1 reduced initiation and progression independent of Nrf2 status, but surprisingly did not completely abrogate tumor formation. Thus, the thioredoxin and glutathione antioxidant systems play unique roles in tumor initiation and progression.

Excessive reactive oxygen species (ROS) are closely associated with the initiation and progression of cancers. As the most abundant intracellular antioxidant, glutathione (GSH) plays a critical role in regulating cellular ROS levels, modulating physiological processes, and is intricately linked to tumor progression and drug resistance. However, the underlying mechanisms remain not fully elucidated. Non-coding RNAs (ncRNAs), including long non-coding RNAs (lncRNAs) and microRNAs (miRNAs), are key regulators of GSH levels. Different ncRNAs modulate various pathways involved in GSH metabolism, and these regulatory targets have the potential to serve as therapeutic targets for enhancing cancer treatment. In this review, we summarize the functions of GSH metabolism and highlight the significance of ncRNA-mediated regulation of GSH in cancer progression, drug resistance, and clinical applications.

Cancer stem cells (CSCs) are a subpopulation with self-renewal and differentiation capacities believed to be responsible for tumor initiation, progression, and recurrence. These cells exhibit unique metabolic features that contribute to their stemness and survival in hostile tumor microenvironments. Like non-stem cancer cells, CSCs primarily rely on glycolysis for ATP production, akin to the Warburg effect. However, CSCs also show increased dependence on alternative metabolic pathways, such as oxidative phosphorylation (OXPHOS) and fatty acid metabolism, which provide necessary energy and building blocks for self-renewal and therapy resistance. The metabolic plasticity of CSCs enables them to adapt to fluctuating nutrient availability and hypoxic conditions within the tumor. Recent studies highlight the importance of these metabolic shifts in maintaining the CSC phenotype and promoting cancer progression. The CSC model suggests that a small, metabolically adaptable subpopulation drives tumor growth and therapy resistance. CSCs can switch between glycolysis and mitochondrial metabolism, enhancing their survival under stress and dormant states. Targeting CSC metabolism offers a promising therapeutic strategy; however, their adaptability complicates eradication. A multi-targeted approach addressing various metabolic pathways is essential for effective CSC elimination, underscoring the need for further research into specific CSC markers and mechanisms that distinguish their metabolism from normal stem cells for successful therapeutic intervention.

Malignant neoplasms constitute a substantial health concern for the human population, currently ranking as the second leading cause of mortality worldwide. In 2022, approximately 10 million deaths were attributable to cancer, and projections estimate that this number will rise to 35 million in 2050. Consequently, the development of effective cancer treatments and prevention strategies remains a primary focus of medical research. In this context, the impacts on the redox balance are being considered. The objective of this study was to present the current knowledge on oxidation and reduction processes in cancer. This review discloses the intricate and multifaceted interplay of oxidoreductive systems during carcinogenesis, which engenders discordant findings in the domain of tumor prevention and treatment. This study also examines the controversies surrounding the use of antioxidants, including their impact on other therapeutic interventions. The review offers a comprehensive overview of the existing knowledge on the subject, concluding that personalized and precise anticancer therapies targeting the redox processes can serve as both effective diagnostic and therapeutic tools.

T cell activation requires a substantial increase in NAD+ production, often exceeding the capacity of oxidative phosphorylation (OXPHOS). To investigate how T cells adapt to this metabolic challenge, we generate T cell-specific ADP/ATP translocase-2 knockout (Ant2-/-) mice. Loss of Ant2, a crucial protein mediating ADP/ATP exchange between mitochondria and cytoplasm, induces OXPHOS restriction by limiting ATP synthase activity, thereby impeding NAD+ regeneration. Interestingly, Ant2-/- naïve T cells exhibit enhanced activation, proliferation and effector functions compared to wild-type controls. Metabolic profiling reveals that these T cells adopt an activated-like metabolic program with increased mitobiogenesis and anabolism. Lastly, pharmacological inhibition of ANT in wild-type T cells recapitulates the Ant2-/- phenotype and improves adoptive T cell therapy of cancer in mouse models. Our findings thus suggest that Ant2-deficient T cells bypass the typical metabolic reprogramming required for activation, leading to enhanced T cell function and highlighting the therapeutic potential of targeting ANT for immune modulation.

Phthalates exposure is a major public health concern due to the accumulation in the environment and associated with levels of testosterone reduction, leading to adverse pregnancy outcomes. However, the relationship between phthalate-induced testosterone level decline and ferroptosis remains poorly defined.

Herein, we aimed to explore the mechanisms of phthalates-induced testosterone synthesis disorder and its relationship to ferroptosis.

We conducted validated experiments in vivo male mice model and in vitro mouse Leydig TM3 cell line, followed by RNA sequencing and metabolomic analysis. We evaluated the levels of testosterone synthesis-associated enzymes and ferroptosis-related indicators by using qRT-PCR and Western blotting. Then, we analyzed the lipid peroxidation, ROS, Fe2+ levels and glutathione system to confirm the occurrence of ferroptosis.

In the present study, we used di (2-ethylhexyl) phthalate (DEHP) to identify ferroptosis as the critical contributor to phthalate-induced testosterone level decline. It was demonstrated that DEHP caused glutathione metabolism and steroid synthesis disorders in Leydig cells. As the primary metabolite of DEHP, mono-2-ethylhexyl phthalate (MEHP) triggered testosterone synthesis disorder accompanied by a decrease in the expression of solute carri1er family 7 member 11 (SLC7A11) protein. Furthermore, MEHP synergistically induced ferroptosis with Erastin through the increase of intracellular and mitochondrial ROS, and lipid peroxidation production. Mechanistically, overexpression of SLC7A11 counteracts the synergistic effect of co-exposure to MEHP-Erastin.

Our research results suggest that MEHP does not induce ferroptosis but synergizes Erastin-induced ferroptosis. These findings provide evidence for the role of ferroptosis in phthalates-induced testosterone synthesis disorder and point to SLC7A11 as a potential target for male reproductive diseases. This study established a correlation between ferroptosis and phthalates cytotoxicity, providing a novel view point for mitigating the issue of male reproductive disease and "The Global Plastic Toxicity Debt".

Disulfidptosis, a regulated cell death modality driven by the cystine transporter solute carrier family 7 member 11 (SLC7A11), is characterized by actin cytoskeleton collapse under glucose starvation. This review systematically elucidates the pivotal role of disulfidptosis in tumor metabolic reprogramming, with a focus on its molecular mechanisms and distinctions from other cell death pathways. The core mechanisms include SLC7A11-mediated cystine overload and NRF2/c-Myc-regulated pentose phosphate pathway activation. By integrating multiomics data and single-cell transcriptomics, we comprehensively decipher the heterogeneous expression patterns of disulfidptosis-related genes (DRGs) and their dynamic interplay with immune microenvironment remodeling. Furthermore, the coexpression networks of DRGs and disulfidptosis-related long noncoding RNAs (DRLs) offer novel insights into tumor diagnosis, prognosis, and targeted therapy. Therapeutically, SLC7A11 inhibitors (e.g., HG106) and glucose transporter inhibitors (e.g., BAY-876) demonstrate efficacy by exploiting metabolic vulnerabilities, whereas natural compounds synergizing with immune checkpoint blockade provide strategies to counteract immunosuppressive microenvironments. Through interdisciplinary collaboration and clinical translation, disulfidptosis research holds transformative potential in redefining precision oncology.

Metastasis is an inefficient process requiring cancer cells to adapt metabolically for survival and colonization in new environments. The contributions of tumor metabolic reprogramming to lymph node (LN) metastasis and its underlying mechanisms remain elusive. Through single-cell RNA sequencing, we identified rare metastasis-initiating cells (MICs) with stem-like properties that drive early LN metastasis. Integrated transcriptome, lipidomic, metabolomic, and functional analyses demonstrated that MICs depend on oxidative phosphorylation (OXPHOS) fueled by fatty acid oxidation (FAO) in the lipid-rich LN microenvironment. Mechanistically, the NRF2-SLC7A11 axis promotes glutathione synthesis to mitigate oxidative stress, thereby enhancing stress resistance and metastatic potential of MICs. Inhibition of NRF2-SLC7A11 reduced LN metastasis and sensitized tumors to cisplatin. Clinically, elevated NRF2-SLC7A11 expression was observed in tumors, with high expression correlating with LN metastasis, chemoresistance, and poor prognosis in esophageal squamous cell carcinoma (ESCC). These findings highlight the pivotal roles of FAO-fueled OXPHOS and NRF2 in LN metastasis and suggest targeting these pathways as a promising therapeutic strategy for metastatic ESCC.

Ferroptosis is a necrotic, non-apoptotic cell death modality triggered by unrestrained iron-dependent lipid peroxidation. By unveiling the regulatory mechanisms of ferroptosis and its relevance to various diseases, research over the past decade has positioned ferroptosis as a promising therapeutic target. The rapid growth of this research field presents challenges, associated with potentially inadequate experimental approaches that may lead to misinterpretations in the assessment of ferroptosis. Typical examples include assessing whether an observed phenotype is indeed linked to ferroptosis, and selecting appropriate animal models and small-molecule modulators of ferroptotic cell death. This Expert Recommendation outlines state-of-the-art methods and tools to reliably study ferroptosis and increase the reproducibility and robustness of experimental results. We present highly validated compounds and animal models, and discuss their advantages and limitations. Furthermore, we provide an overview of the regulatory mechanisms and the best-studied players in ferroptosis regulation, such as GPX4, FSP1, SLC7A11 and ACSL4, discussing frequent pitfalls in experimental design and relevant guidance. These recommendations are intended for researchers at all levels, including those entering the expanding and exciting field of ferroptosis research.

Aims: Itaconate (IA) is synthesized in the citric acid cycle via cis-aconitate decarboxylase (ACOD1); however, its biological significance in cancer remains incompletely understood. In previous studies, 4-octyl itaconate (OI) was used as a membrane-permeable form of IA, but little detailed verification of the difference in biological activities between IA and OI exists. Here, we investigated the direct effects of IA and OI on melanoma. Results: The proliferation of melanoma cells treated with OI was significantly suppressed in vitro, and our transcriptomic analysis revealed drastic changes in the expression of glutathione metabolism-related genes in OI-treated cells. Indeed, OI treatment decreased intracellular glutathione levels, followed by increased production of reactive oxygen species and expression of γH2AX, a marker of DNA damage, and β-galactosidase, a marker of cellular senescence. We further showed that the mitochondrial respiratory capacity in B16 cells was significantly decreased by OI treatment. OI administration also suppressed the growth of B16 tumor transplants in vivo, and the expression of γH2AX was increased in tumor tissues of OI-treated mice. In addition, minimal effects of OI treatment were observed in melanocytes and normal tissues. We also proved that not only exogenous IA, which enters intracellularly, but also endogenous IA has little effect on melanoma proliferation activity, via an investigation using Acod1-overexpressing transfectants and Acod1-deficient mice. Conclusion: This work revealed that OI disrupts the antioxidant system via the collapse of glutathione metabolism and inhibits cancer cell proliferation. Antioxid. Redox Signal. 42, 547-565.

Rictor/mTORC2 has been demonstrated to have important roles in cancer development and progression in a number of solid and hematologic malignancies. However, little is known about the role of Rictor/mTORC2 in ovarian cancer pathophysiology. Herein, using conditional Rictor knockout mice, we were able to demonstrate that Rictor deletion disrupted glutathione metabolism through AKT/Nrf2 signaling pathway and induced intracellular oxidative stress during the malignant transformation of Kras/Pten-mutant ovarian surface epithelial cells. Elevated reactive oxygen species and activated FOXO3a in Rictor-deleted cells strikingly shifts the functional interaction of β-catenin from TCF to FOXO3a, which strongly inhibits classical Wnt/β-catenin signaling. Our findings emphasize a pivotal role for Rictor in orchestrating crosstalk between the PI3K/AKT and Wnt/β-catenin signaling in the development of ovarian cancer. Illustration of Rictor/mTORC2 in promoting tumor onset by regulating glutathione metabolism and mediating oncogenic signaling.

Ferroptosis is an iron-dependent form of regulated cell death characterized by the accumulation of iron-dependent lipid peroxides, which has been implicated in the pathogenesis of various diseases, and therapeutic agents targeting ferroptosis are emerging as promising tools for cancer treatment. Current research reveals that ferroptosis-targeted therapies can effectively inhibit tumor progression or delay cancer development. Notably, natural product-derived compounds-such as artemisinin, baicalin, puerarin, quercetin, kaempferol, and apigenin-have demonstrated the ability to modulate ferroptosis, offering potential anti-cancer benefits. Mechanistically, ferroptosis exhibits negative glutathione peroxidase 4 (GPX4) regulation and demonstrates a positive correlation with plasma membrane polyunsaturated fatty acid (PUFA) abundance. Moreover, the labile iron pool (LIP) serves as the redox engine of ferroptosis. This review systematically analyzes the hallmarks, signaling pathways, and molecular mechanisms of ferroptosis, with a focus on how natural product-derived small molecules regulate this process. It further evaluates their potential as ferroptosis inducers or inhibitors in anti-tumor therapy, providing a foundation for future clinical translation.

Evolutionarily conserved selenoprotein O (SELENOO) catalyzes a posttranslational protein modification known as AMPylation that is essential for the oxidative stress response in bacteria and yeast. Given that oxidative stress experienced in the blood limits survival of metastasizing melanoma cells, SELENOO might be able to affect metastatic potential. However, further work is needed to elucidate the substrates and functional relevance of the mammalian homolog of SELENOO. In this study, we revealed that SELENOO promotes cancer metastasis and identified substrates of SELENOO in mammalian mitochondria. In patients with melanoma, high SELENOO expression was correlated with metastasis and poor overall survival. In a murine model of spontaneous melanoma metastasis, SELENOO deficiency significantly reduced metastasis to distant visceral organs, which could be rescued by treatment with the antioxidant N-acetylcysteine. Mechanistically, SELENOO AMPylated multiple mitochondrial substrates, including succinate dehydrogenase subunit A, one of the four key subunits of mitochondrial complex II. Consistently, SELENOO-deficient cells featured increased mitochondrial complex II activity. Together, these findings demonstrate that SELENOO deficiency limits melanoma metastasis by modulating mitochondrial function and oxidative stress. Significance: SELENOO alters mitochondrial function and supports metastasis in melanoma, highlighting the impact of SELENOO-mediated posttranslational modification of mitochondrial substrates and selenoproteins in cancer progression.

Chronic myeloid leukemia (CML) is a type of malignancy characterized by harboring the oncogene Bcr-Abl, which encodes the constitutively activated tyrosine kinase BCR-ABL. Although tyrosine kinase inhibitors targeting BCR-ABL have revolutionized CML therapy, native and acquired drug resistance commonly remains a great challenge. Thioredoxin 1 (Trx1) and glutamate-cysteine ligase (GCL), which are two major antioxidants that maintain cellular redox homeostasis, are potential targets for cancer therapy and overcoming drug resistance. However, how their inhibition is implicated in CML is still unclear. Here, our results revealed that Trx1 was overexpressed in patients with CML compared with healthy donors. Trx1 expression was greater in imatinib-resistant CML cells than in imatinib-sensitive cells. Pharmacological inhibitors of Trx1 attenuated cell growth and reduced colony formation in both imatinib-sensitive and imatinib-resistant CML cells. Furthermore, decreased Trx1 expression enhanced the cytotoxicity of the GCL inhibitor buthionine sulfoximine (BSO). We surmise that the combined inhibition of Trx1 and GCL promotes the induction of hydrogen peroxide and depletes GPX4 expression in CML cells, resulting in ferroptosis in cancerous cells. Finally, the combined inhibition of Trx1 and GCL had a synergistic effect on CML cells in murine xenograft models. These findings offer crucial informationregarding the combined roles ofTrx1 and GCL in triggering ferroptosis in CML and suggestefficacioustherapeutic uses for these systems in this disease.

Resistance to chemotherapy is an important challenge in the clinical management of triple-negative breast cancer (TNBC). Utilization of the amino acid glutamine as a key nutrient is a metabolic signature of TNBC featuring high glutaminase (GLS) activity and a large pool of cellular glutamate, which mediates intracellular enrichment of cystine via xCT (SLC7A11) antiporter activity. To overcome chemo-resistant TNBC, we identified a strategy of dual metabolic inhibition of GLS and xCT to sensitize resistant TNBC cells to chemotherapy. We successfully tested this strategy in a human TNBC line and its chemoresistant variant in vitro and their xenograft models in vivo. Key findings of our study include: 1. Dual metabolic inhibition induced pronounced reductions of cellular glutathione accompanying significant increases of cellular superoxide level in both parent and resistant TNBC cells. While GLS and xCT inhibition did not directly kill cells via apoptosis, they potentiated doxorubicin (DOX) and cisplatin (CIS) to induce remarkably higher levels of apoptosis than DOX or CIS alone. 2. Although the resistant TNBC cells exhibited higher capacity to mitigate oxidative stress than the parent cells, their resistance was overcome by dual metabolic inhibition combined with DOX or CIS. 3. In vivo efficacy and safety of the triple combination (GLS and xCT inhibition plus DOX or CIS) were demonstrated in both chemo sensitive and resistant TNBC tumors in mice. In conclusion, GLS and xCT inhibition resulted in unmitigated oxidative stress due to depletion of glutathione, representing a promising strategy to overcome chemoresistance in glutamine-dependent TNBC.

Asthma and chronic obstructive pulmonary disease (COPD) are heterogeneous obstructive diseases characterized by airflow limitations and are recognized as significant contributors to fatality all over the globe. Asthma accounts for about 4, 55,000 deaths, and COPD is the 3rd leading contributor of mortality worldwide. The pathogenesis of these two obstructive disorders is complex and involves numerous mechanistic pathways, including inflammation-mediated and non-inflammation-mediated pathways. Among all the pathological categorizations, programmed cell deaths (PCDs) play a dominating role in the progression of these obstructive diseases. The two major PCDs that are involved in structural and functional remodeling in the progression of asthma and COPD are Pyroptosis and Ferroptosis. Pyroptosis is a PCD mechanism mediated by the activation of the Nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3) inflammasome, leading to the maturation and release of Interleukin-1β and Interleukin-18, whereas ferroptosis is a lipid peroxidation-associated cell death. In this review, the major molecular pathways contributing to these multifaceted cell deaths have been discussed, and crosstalk among them regarding the pathogenesis of asthma and COPD has been highlighted. Further, the possible therapeutic approaches that can be utilized to mitigate both cell deaths at once have also been illustrated.

Prostate cancer stem cells (CSCs) play an important role in cancer cell survival, proliferation, metastasis, and recurrence; thus, removing CSCs is important for complete cancer removal. However, the mechanisms underlying CSC functions remain largely unknown, making it difficult to develop new anticancer drugs targeting CSCs. Herein, we aimed to identify novel factors that regulate stemness and predict prognosis.

We reanalyzed 2 single-cell RNA sequencing data of prostate cancer (PCa) tissues using Seurat. We used gene set enrichment analysis (GSEA) to estimate CSCs and identified common upregulated genes in CSCs between these datasets. To investigate whether its expression levels change over CSC differentiation, we performed a trajectory analysis using monocle 3. In addition, GSEA helped us understand how the identified genes regulate stemness. Finally, to assess their clinical significance, we used the Cancer Genome Atlas database to evaluate their impact on prognosis.

The expression of thioredoxin (TXN), a redox enzyme, was approximately 1.2 times higher in prostate CSCs than in PCa cells (P < 1 × 10-10), and TXN expression decreased over CSC differentiation. In addition, GSEA suggested that intracellular signaling pathways, including MYC, may be involved in stemness regulation by TXN. Furthermore, TXN expression correlated with poor prognosis (P < .05) in PCa patients with high stemness.

Despite the limited sample size in our study and the need for further in vitro and in vivo experiments to demonstrate whether TXN functionally regulates prostate CSCs, our findings suggest that TXN may serve as a novel therapeutic target against CSCs. Moreover, TXN expression in CSCs could be a useful marker for predicting the prognosis of PCa patients.

Drug resistance is a major barrier to cancer therapies and remains poorly understood. Recently, non-mutational mechanisms of drug resistance have been proposed where a more plastic metabolic response can play a major role. Here, we show that upon drug resistance, glioblastoma (GBM) cells have increased oxidative stress, mitochondria function, and protein aggregation. Gamma (γ)-glutamylcyclotranserase (GGCT), an enzyme in the γ-glutamyl cycle for glutathione production, located on chromosome 7 which is commonly amplified in GBM is also increased upon resistance. We further observe that the byproduct of GGCT-pyroglutamic acid-can bind aggregating proteins and that genetic and pharmacological inhibition of GGCT prevents protein aggregation. Finally, we found increased protein aggregation, GGCT expression, and pyroglutamic acid staining in recurrent GBM patient samples, adjacent non-tumor brain, and Alzheimer's brains. These findings suggest a new pathway for protein aggregation within drug resistant brain cancer that should be further studied in other brain disorders.

We recently observed an inverse and time-dependent association between systemic oxidative stress (OxS), measured by urinary biomarkers of nucleic acid oxidation, and colorectal cancer (CRC) risk. Further investigations into other types of OxS markers are warranted.

To extend the investigation into systemic lipid peroxidation and CRC risk.

Utilizing a nested case-control design, this study's primary analysis was performed in two large prospective cohorts in Shanghai, China, and replicated in an independent cohort in the US.

Systemic lipid peroxidation was assessed by urinary F 2 -isoprostanes (F 2 -IsoPs) using UPLC-MS/MS assays.

During 15.1-year follow-up in the Shanghai cohorts, 1938 incident CRC cases were identified and matched to one control each through incidence-density sampling. In the US cohort, 285 incident CRC cases were included, each matched to two controls. Odds ratios (ORs) for CRC were calculated using multivariable conditional logistic regression models.

Elevated levels of urinary 5-F 2t -IsoP (5-iPF 2α -VI), a major isomer of F 2 -IsoPs induced solely by free radicals, were associated with reduced risk of CRC in the Shanghai cohorts. This finding was replicated in the US cohort. Moreover, this inverse association was time-dependent, manifesting only in the later years of cancer development. Multivariable-adjusted ORs (95% CI) for CRC diagnosed within 5 years of enrollment at the 10th and 90th percentiles of 5-F 2t -IsoP levels, relative to the median, were 1.57 (1.26-1.96) and 0.61 (0.42-0.89), respectively, indicating a 2.2-fold difference in risk between the two groups. A stronger association was observed when using the composite index of DNA, RNA and lipid OxS markers, showing a 3.9-fold difference in risk between the two groups. No significant association was found for CRC diagnosed beyond 5 years of enrollment.

This study provides new evidence that systemic OxS is inversely and time-dependently associated with CRC risk in humans.

Question: Is the time-dependent relationship between oxidative stress and tumorigenesis observed at the cellular level in experimental models also present at the systemic level in a population-based setting?Findings: Elevated systemic lipid peroxidation, measured by urinary F 2 -isoprostanes, was associated with a reduced risk of colorectal cancer (CRC) in two large prospective cohort studies in Shanghai, China, which was replicated in an independent cohort in the United States. This association varied over time, showing a stronger effect as cancer advanced. Meaning: This study provides new evidence that systemic oxidative stress is inversely and time-dependently associated with CRC risk in humans.

The incidence of gastric cancer remains high and poses a serious threat to human health. Recent comprehensive investigations into amino acid metabolism and immune system components within the tumor microenvironment have elucidated the functional interactions between tumor cells, immune cells, and amino acid metabolism. This study reviews the characteristics of amino acid metabolism in gastric cancer, with a particular focus on the metabolism of methionine, cysteine, glutamic acid, serine, taurine, and other amino acids. It discusses the relationship between these metabolic processes, tumor development, and the body's anti-tumor immunity, and analyzes the importance of targeting amino acid metabolism in gastric cancer for chemotherapy and immunotherapy.

Alterations of metabolism, including changes in mitochondrial metabolism as well as glutathione (GSH) metabolism are a well appreciated hallmark of many cancers. Mitochondrial GSH (mGSH) transport is a poorly characterized aspect of GSH metabolism, which we investigate in the context of cancer. Existing functional annotation approaches from machine (ML) or deep learning (DL) models based only on protein sequences, were unable to annotate functions in biological contexts.

We develop a flexible ML framework for functional annotation from diverse feature data. This hybrid ML framework leverages cancer cell line multi-omics data and other biological knowledge data as features, to uncover potential genes involved in mGSH metabolism and membrane transport in cancers. This framework achieves strong performance across functional annotation tasks and several cell line and primary tumor cancer samples. For our application, classification models predict the known mGSH transporter SLC25A39 but not SLC25A40 as being highly probably related to mGSH metabolism in cancers. SLC25A10, SLC25A50, and orphan SLC25A24, SLC25A43 are predicted to be associated with mGSH metabolism in multiple biological contexts and structural analysis of these proteins reveal similarities in potential substrate binding regions to the binding residues of SLC25A39.

These findings have implications for a better understanding of cancer cell metabolism and novel therapeutic targets with respect to GSH metabolism through potential novel functional annotations of genes. The hybrid ML framework proposed here can be applied to other biological function classifications or multi-omics datasets to generate hypotheses in various biological contexts. Code and a tutorial for generating models and predictions in this framework are available at: https://github.com/lkenn012/mGSH_cancerClassifiers .

Prostate cancer (PCa) is a kind of malignant solid tumor commonly observed among males worldwide. The dilemma of increasing incidence with therapeutic resistance has become the leading issue in PCa clinical management. Ferroptosis is a new form of regulatory cell death caused by iron-dependent lipid peroxidation, which has a dual role in PCa evolution and treatment due to the multi-omics cascade of interactions among pathways and environmental stimuli. Hence deciphering the role of ferroptosis in carcinogenesis would provide novel insights and strategies for precision medicine and personalized healthcare against PCa. In this study, the mechanisms of ferroptosis during cancer development were summarized both at the molecular and tumor microenvironment level. Then literature-reported ferroptosis-related signatures in PCa, e.g., genes, non-coding RNAs, metabolites, natural products and drug components, were manually collected and functionally compared as drivers/inducers, suppressors/inhibitors, and biomarkers according to their regulatory patterns in PCa ferroptosis and pathogenesis. The state-of-the-art techniques for ferroptosis-related data integration, knowledge identification, and translational application to PCa theranostics were discussed from a combinative perspective of artificial intelligence-powered modelling and advanced material-oriented therapeutic scheme design. The prospects and challenges in ferroptosis-based PCa researches were finally highlighted to light up future wisdoms for the flourishing of current findings from bench to bedside.

Mounting evidence shows that tumor growth and progression rely on thioredoxin reductase 1 (TXNRD1)-mediated detoxification of oxidative stress that results from deregulated metabolism and mitogenic signaling in tumors. TXNRD1 levels are significant higher in triple negative breast cancer (TNBC) compared to normal tissue, making TXNRD1 a compelling TNBC therapeutic target. Despite the many attempts to generate TXNRD1 inhibitors, all known and reported compounds inhibiting TXNRD1 are problematic; they interact with TXNRD1 irreversibly and non-specifically resulting in numerous adverse side effects. Recently, a series of breakthrough studies identified a novel regulatory site, the 'doorstop pocket', in Schistosoma mansoni thioredoxin glutathione reductase, a TXNRD-like enzyme and an established drug target for the human parasitic infection, schistosomiasis. This discovery underpins the development of new first-in-class non-covalent inhibitors for this family of enzymes. Our data show that novel non-covalent TXNRD inhibitors (TXNRD(i)s) are potent dose-dependent inhibitors of viability in cellular models of TNBC. TXNRD(i)s attenuate several aggressive cancer phenotypes such as, clonogenic survival, mammosphere forming efficiency, invasion, and TXNRD-related gene expression in TNBC cells. TXNRD(i)s engage and inhibit TXNRD1 in live TNBC cells and xenograft tumors, thus supporting the mechanism of action at a cellular level. More importantly, TXNRD(i)s attenuated tumor growth in a preclinical MDA-MB-231 TNBC xenograft mouse model. Although additional optimization for TXNRD(i)s' potency is warranted, these results may open a new avenue for the development of novel small molecule therapeutics for TNBC.

Acquired resistance poses a significant obstacle to the effectiveness of platinum-based treatment for cancers. As the most abundant antioxidant, glutathione (GSH) enables cancer cell survival and chemoresistance, by scavenging excessive reactive oxygen species (ROS) induced by platinum. Therapeutic strategy targeting GSH synthesis has been developed, however, failed to produce desirable effects in preventing cancer progression. Thus, uncovering mechanisms of rewired GSH metabolism may aid in the development of additional therapeutic strategies to overcome or delay resistance. Here, we identify upregulation of long noncoding RNA (lncRNA) GDIL (GSH Degradation Inhibiting LncRNA) in platinum resistant colorectal cancer (CRC) and ovarian cancer cells compared with parental ones. High expression of GDIL in resistant CRC is associated with poor survival and hyposensitivity to chemotherapy. We demonstrate that GDIL boosted GSH levels and enhances clearance of ROS induced by platinum. Metabolomic and metabolic flux analysis further reveals that GDIL promotes GSH accumulation by inhibiting GSH degradation. This is attributed by downregulation of CHAC1, an enzyme that specifically degrades intracellular GSH. Mechanistically, GDIL binds and re-localizes the nuclear protein XRN2 to the cytoplasm, where GDIL further serve as a scaffold for XRN2 to identify and degrade CHAC1 mRNA. Suppression of GDIL with selective antisense oligonucleotide, restored drug sensitivity in platinum resistant cell lines and delayed drug resistance in cell line- and patient-derived xenografts. Thus, lncRNA GDIL is a novel target to promote GSH degradation and augment platinum therapy.

The Yishenjiangya formula (YSJ) is a traditional Chinese medicine (TCM) primarily composed of qi-tonifying components. This classic formula is commonly utilized to treat kidney qi deficiency in elderly patients with hypertension. According to TCM, maintaining a balance between qi and blood is crucial for stable blood pressure. Kidney qi deficiency can disrupt this balance, altering fluid shear force and, ultimately, leading to hypertension, particularly in elderly populations. Despite YSJ's efficacy in treating hypertension, its specific anti-hypertensive mechanisms remain unclear.

YSJ is commonly prescribed for elderly patients with hypertension. Earlier metabolomics studies demonstrated that YSJ exerts antihypertensive effects by influencing four key pathways: linoleic acid metabolism, glycerol phospholipid metabolism, arginine and proline metabolism, and steroid hormone biosynthesis. This study aims to combine metabolomic and proteomic analyses to thoroughly understand the molecular biological mechanisms responsible for YSJ's anti-hypertensive properties.

Ultra-Performance Liquid Chromatography-Mass Spectrometry (UPLC-MS) metabolomics, combined with Label-Free Quantitation (LFQ) proteomics, was employed to analyze serum samples from elderly individuals with and without hypertension pre- and post-YSJ intervention. Serum levels of candidate proteins were assessed using enzyme-linked immunosorbent assay, and receiver operating characteristic curves were used to evaluate the diagnostic performance of the target proteins.

Eight differentially expressed metabolites and three differentially expressed proteins were identified as potential therapeutic targets of YSJ. These substances are primarily involved in unsaturated fatty acid metabolism, fluid shear stress and atherosclerosis pathway, primary bile acid biosynthesis, proline metabolism, apoptosis, and endoplasmic reticulum stress. YSJ exerts its therapeutic effects on hypertension in the elderly by modulating these pathways.

YSJ effectively treats senile hypertension. By analyzing the correlation between therapeutic targets and pathways, YSJ's anti-hypertensive effect was achieved by inhibiting lipid peroxidation and matrix degeneration. Combining metabolomics and proteomics provides an effective method for uncovering YSJ's anti-hypertensive mechanisms.

Randomized controlled trials have failed to validate that neutralizing oxidative stress (OxS) through antioxidant supplementation reduces cancer risk. This study aims to prospectively investigate whether the relationship between systemic OxS and colorectal cancer (CRC) risk changes over the course of cancer development.

This study utilized a nested case-control design in two Shanghai cohorts for primary analysis and one US cohort for replication analysis. During a median follow-up of 15.1 years in the Shanghai cohorts, 1938 incident CRC cases were identified and matched to one control each. In the US cohort, 285 incident CRC cases were included with two matched controls per case. Systemic OxS was assessed by urinary markers of DNA oxidation (8-oxo-7,8-dihydro-2'-deoxyguanosine [8-oxo-dG]) and RNA oxidation (7,8-dihydro-8-oxo-guanosine [8-oxo-Guo]) using UPLC-MS/MS assays. Multivariable-adjusted odds ratios (ORs) for CRC risk were calculated.

After adjusting for potential confounders, we observed an inversion association between OxS markers and CRC risk in the Shanghai cohorts, which was independently replicated in the US cohort. Moreover, the inverse association was time-dependent, manifesting only for CRC cases diagnosed within 5 years of enrollment. ORs (95% CI) for CRC at the 10th and 90th percentiles of 8-oxo-dG levels, relative to the median, were 1.87 (1.39 to 2.53) and 0.48 (0.37 to 0.63), respectively, demonstrating an approximate 4-fold difference in risk between the two groups, with P for overall association of < 0.001. A similar pattern was observed for 8-oxo-Guo. No significant association was found for CRC diagnosed beyond 5 years of enrollment.

This novel finding of an inverse and time-dependent relationship between systemic OxS and CRC risk, if further confirmed, may provide a new perspective for revisiting redox-based chemoprevention.

Background: Almost all large randomized controlled trials have failed to validate the hypothesis that neutralizing oxidative stress through antioxidant supplementation can lower cancer risk, which has puzzled the public and researchers for decades.Key Findings: A reduced risk for colorectal cancer (CRC) with increasing systemic oxidative stress, measured by two urinary biomarkers of DNA and RNA oxidation, was observed in two large prospective cohort studies in Shanghai, China, and was replicated in an independent cohort in the United States. This association was time-dependent, with the inverse relationship strengthening as the biomarker assessment neared the time of CRC diagnosis.Relevance: Our study, for the first time, suggests an inverse and time-dependent relationship between systemic oxidative stress and CRC development, which, if further confirmed, may provide a new perspective for revisiting redox-based chemoprevention.

Common features of the aging heart are dysregulated metabolism, inflammation, and fibrosis. Elevated oxidative stress is another hallmark of cardiac aging that can exacerbate each of these conditions. We hypothesize that by increasing natural antioxidant levels (glutathione), we will improve cardiac function. Twenty-one-month-old mice were fed glycine and N-acetyl cysteine (GlyNAC; glutathione precursors)-supplemented or control diets for 12 weeks. Heart function was monitored longitudinally, and the exercise performance was determined at the end of the study. We found that the GlyNAC diet was beneficial for old male but not old female mice, leading to an increase of Ndufb8 expression (a subunit of the mitochondrial respiratory chain complex), and higher enzymatic activity for CPT1b and CrAT, 2 carnitine acyltransferases that are critical to cardiomyocyte metabolism. Although no quantifiable change of collagen turnover was detected, hearts from GlyNAC-fed old males exhibited a slight but significant enrichment in Fmod, a protein that can inhibit collagen fibril formation, possibly reducing extracellular matrix stiffness and thus improving diastolic function. Cardiac diastolic function was modestly improved in males but not females, and surprisingly GlyNAC-fed female mice showed a decline in exercise performance. In summary, our work supports the concept that aged male and female hearts are phenotypically different. These basic differences may affect the response to pharmacological and diet interventions, including antioxidants.

Thioredoxin1 (TRX1) and telomerase are both attractive oncology targets that are tightly implicated in tumor initiation and development. Here, we reported that the 6-dithio-2-deoxyguanosine analog thiotert exhibits an effective cytotoxic effect on myelodysplastic syndromes (MDS) cell SKM-1 and lymphoma cell U-937. Further studies confirmed that thiotert effectively disrupts cellular redox homeostasis, as evidenced by elevated intracellular reactive oxygen species (ROS) levels, increased MnSOD, accelerated DNA impairment, and activated apoptosis signal. Mechanistically, our present study revealed that thiotert treatment effectively inhibited the function of the TRX1/TRXR1 system and telomerase reverse transcriptase (TERT), rendering oxidative damage and impairment of telomeres. Meanwhile, pharmacological administration of glutathione (GSH), N-acetylcysteine (NAC), and mitoquinone (MitoQ), or genetic overexpression of TRX1 or TERT in MDS and cells could dampen the toxicity caused by thiotert. Remarkably, the in vivo mouse model of MDS demonstrated that thiotert administration exhibited greater efficacy in tumor reduction compared to the conventional chemotherapy drug cytarabine. Collectively, these results provide experimental insights into the mechanism of thiotert-induced MDS and lymphoma cell death and unveil that thiotert may be an effective and promising new drug for future MDS and lymphoma treatment.

Reactive oxygen species (ROS) is promising in cancer therapy by accelerating tumor cell death, whose therapeutic efficacy, however, is greatly limited by the hypoxia in the tumor microenvironment (TME) and the antioxidant defense. Amplification of oxidative stress has been successfully employed for tumor therapy, but the interactions between cancer cells and the other factors of TME usually lead to inadequate tumor treatments. To tackle this issue, we develop a pH/redox dual-responsive nanomedicine based on the remodeling of cancer-associated fibroblasts (CAFs) for multi-pronged amplification of ROS (ZnPP@FQOS). It is demonstrated that ROS generated by ZnPP@FQOS is endogenously/exogenously multiply amplified owing to the CAFs remodeling and down-regulation of anti-oxidative stress in cancer cells, ultimately achieving the efficient photodynamic therapy in a female tumor-bearing mouse model. More importantly, ZnPP@FQOS is verified to enable the stimulation of enhanced immune responses and systemic immunity. This strategy remarkably potentiates the efficacy of photodynamic-immunotherapy, thus providing a promising enlightenment for tumor therapy.

Hyaluronic acid (HA) nanogels have attracted widespread attention, aiming to improve cancer treatment paradigms and overcome the limitations of free-form drugs. However highly hydrophilic nature of HA nanogels limits their potential application where amphiphilic interactions are required for the delivery of hydrophobic drugs. In this study, we developed amphiphilic structure oxaliplatin (OXA) loaded oligo-hyaluronic acid (oHA)-PEG-Octane nanogel using stable disulfide bonds with ultrasonic re-emulsion method. 1,8-Mercaptooctane present in the organic phase underwent crosslinking with sulfhydryl groups conjugated on oHA and PEG in the inner aqueous phase through interfacial reactions, resulting in the formation of an amphiphilic structure of the nanogels. The nanogels demonstrated uniform size, stability, excellent biocompatibility, and achieved a high drug-loading capacity of 10.8 %. OXA NGs targeted tumor cells through CD44-mediated endocytosis, disassembled under the influence of high glutathione (GSH) levels within the tumor microenvironment (TME) and released OXA inside the reductive cytosol to trigger immunogenic cell death (ICD) of tumor cells. In vivo experiments showed OXA NGs could inhibit tumor growth. Furthermore, the amphiphilic hyaluronic acid nanohydrogel may have clinical potential due to its ability to accommodate various therapeutic agents; therefore, OXA NGs are a potential candidate for clinical translation.

Mutation of genes related to the SWI/SNF chromatin remodeling complex is detected in 20% of all cancers. The SWI/SNF chromatin remodeling complex comprises about 15 subunits and is classified into three subcomplexes: cBAF, PBAF, and ncBAF. Previously, we showed that ovarian clear cell carcinoma cells deficient in ARID1A, a subunit of the cBAF complex, are synthetic lethal with several genes required for glutathione (GSH) synthesis and are therefore sensitive to the GSH inhibitor eprenetapopt (APR-246). However, we do not know whether cancer cells deficient in SWI/SNF components other than ARID1A are selectively sensitive to treatment with eprenetapopt. Here, we show that SMARCA4-, SMARCB1-, and PBRM1-deficient cells are more sensitive to eprenetapopt than SWI/SNF-proficient cells. We found that deficiency of SMARCA4, SMARCB1, or PBRM1 attenuates transcription of the SLC7A11 gene (which supplies cysteine as a raw metabolic material for GSH synthesis) by the failure of recruitment of cBAF and PBAF to the promotor and enhancer regions of the SLC7A11 locus, thereby reducing basal levels of GSH. In addition, eprenetapopt decreased the amount of intracellular GSH and increased the intracellular amount of reactive oxygen species (ROS), followed by induction of apoptosis. Taken together, eprenetapopt could be a promising selective agent for SWI/SNF-deficient cancer cells derived from SMARCA4-deficient lung cancers, SMARCB1-deficient rhabdoid tumors, and PBRM1-deficient kidney cancers.

Chemoradiotherapy is a conventional treatment modality for patients with glioblastoma (GBM). However, the efficacy of this approach is significantly hindered by the development of therapeutic resistance. The thioredoxin system, which plays a crucial role in maintaining redox homeostasis, confers protection to cancer cells against apoptosis induced by chemoradiotherapy. Herein, we demonstrate that sulforaphane (SFN), an isothiocyanate phytochemical with anti-cancer effects, inhibits the activity of thioredoxin reductase 1 (TrxR1) through covalent conjugation with residues C59/64/497&U498. This inhibition of TrxR1 leads to the accumulation of reactive oxygen species (ROS), thereby enhancing chemoradiotherapy-induced apoptosis in GBM cells. Furthermore, SFN-induced ROS accumulation facilitates the polarization of M1-like macrophages, which synergistically sensitize GBM tumors to chemoradiotherapy. In conclusion, our study unveils that SFN has potential benefits in improving the effect of chemoradiotherapy and prognosis for GBM patients by targeting TrxR1.

Background: Targeted therapies (e.g., ibrutinib) have markedly improved chronic lymphocytic leukemia (CLL) management; however, ~20% of patients experience disease relapse, suggesting the inadequate depth and durability of these front-line strategies. Moreover, immunotherapeutic success in CLL has been stifled by its pro-tumor microenvironment milieu and low mutational burden, cultivating poor antigenicity and limited ability to generate anti-tumor immunity through adaptive immune cell engagement. Previously, we have demonstrated how a three-carbon-linker spirocyclic dimer (SpiD3) promotes futile activation of the unfolded protein response (UPR) in CLL cells through immense misfolded-protein mimicry, culminating in insurmountable ER stress and programmed CLL cell death. Method: Herein, we used flow cytometry and cell-based assays to capture the kinetics and magnitude of SpiD3-induced damage-associated molecular patterns (DAMPs) in CLL cell lines and primary samples. Result: SpiD3 treatment, in vitro and in vivo, demonstrated the capacity to propagate immunogenic cell death through emissions of classically immunogenic DAMPs (CALR, ATP, HMGB1) and establish a chemotactic gradient for bone marrow-derived dendritic cells. Conclusions: Thus, this study supports future investigation into the relationship between novel therapeutics, manners of cancer cell death, and their contributions to adaptive immune cell engagement as a means for improving anti-cancer therapy in CLL.