Ferroptosis, a regulated form of cell death dependent on iron and marked by lipid peroxidation, is increasingly recognized for its role in a wide array of diseases, including cancers, neurodegenerative disorders, and tissue damage. This review examines the dynamic interaction between ferroptosis and the Wnt/β-catenin signaling pathway, focusing on how Wnt surface receptors, ligands, antagonists, and associated components influence the regulation of ferroptosis. Key elements such as Frizzled receptors, Wnt ligands, and antagonists like DKK1 are shown to affect ferroptosis by altering oxidative stress, lipid dynamics, and iron metabolism. A central aspect of this interaction is the role of the destruction complex, particularly GSK-3β, which regulates ferroptosis through its upstream modulation by the AKT pathway and downstream control over NRF2, GPX4, and SLC7A11. Furthermore, the involvement of β-catenin/TCF transcription factors in the regulation of ferroptosis emphasizes the significance of this pathway in promoting cell survival and resisting ferroptosis, particularly in various cancers. Multiple cancers, including colorectal, breast, ovarian, and lung cancers, are affected by disruptions in the Wnt/ferroptosis axis, where enhanced Wnt signaling helps cancer cells evade ferroptosis and develop resistance to treatments. Beyond cancer, this axis also plays a crucial role in neurodegenerative diseases and conditions like myocardial infarction. Additionally, natural compounds have shown potential in modulating the Wnt/ferroptosis pathway, offering promising therapeutic approaches for a variety of diseases. This review highlights the molecular mechanisms of the Wnt/ferroptosis axis, paving the way for innovative treatment options in cancer and other diseases.

Extracellular vesicles are nanoscale vesicles released by a diversity of cells that mediate intercellular communication by transporting an array of biomolecules. They are gaining increasing attention in cancer research due to their ability to carry specific biomarkers. This characteristic makes them potentially useful for highly sensitive, noninvasive diagnostic procedures and more precise prognostic assessments. Consequently, EVs are emerging as a transformative tool in cancer treatment, facilitating early detection and personalized medicine. Despite significant progress, clinical implementation is hindered by challenges in EV isolation, purification, and characterization. However, developing advanced biosensor technologies offers promising solutions to these obstacles. This review highlights recent progress in biosensors for EV detection and analysis, focusing on various sensing modalities including optical, electrochemical, microfluidic, nanomechanical, and biological sensors. We also explore techniques for EV isolation, characterization, and analysis, such as electron microscopy, atomic force microscopy, nanoparticle tracking analysis, and single-particle analysis. Furthermore, the review critically assesses the challenges associated with EV detection and put forward future directions, aiming to usher in a cutting-edge era of precision medicine through advanced, sensor-based, noninvasive early cancer diagnosis by detecting EV-carried biomarkers.

Ferroptosis, an iron-dependent cell death pathway distinct from apoptosis, is crucial in breast cancer (BC) research, especially for overcoming resistance in triple-negative breast cancer (TNBC). Unlike traditional apoptosis, ferroptosis involves the glutathione (GSH)/glutathione peroxidase 4 (GPX4) axis, iron-driven oxidative reactions, and phospholipid peroxidation. TNBC, characterized by the absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), is particularly prone to ferroptosis due to acyl-coenzyme A synthetase (ACSL) 4-related lipid changes and solute carrier family 7 member 11 (SLC7A11)-mediated cystine transport. Recent advancements in biomarkers and therapeutic strategies targeting ferroptosis hold significant promise for the diagnosis and prognosis of TNBC. Notable innovations encompass the development of small-molecule compounds and various methodologies designed to enhance ferroptosis. Combination therapies have demonstrated improved antitumor efficacy by counteracting chemotherapy resistance and inducing immunogenic cell death. Nonetheless, challenges persist in optimizing drug delivery mechanisms and minimizing off-target effects. This review underscores the progress in ferroptosis research and proposes precision oncology strategies that exploit metabolic flexibility in BC, intending to transform TNBC treatment and enhance therapeutic outcomes.

Cancer stem cells (CSCs) are a major cause for the insufficient tumor eradication in the clinic, which universally present enhanced mitochondrial oxidative phosphorylation (OXPHOS) to facilitate stemness maintenance and drive treatment resistance. Herein, we report a nanointegrative radiation-triggerable bioreactor (RTB) that selectively remodels CSC-intrinsic arginine metabolism to bioenergetically reprogram CSCs towards a therapeutically-vulnerable differentiated state, leading to durable radio-immunotherapeutic responses in vivo. The RTB nanosystem was developed through the supramolecular integration of radioresponsive iNOS-expressing genetic circuits (pDNAiNOS) and β-lapachone (LAP) into CSC-targeting cationic liposomes. Low-dose radiotherapy (LDR)-induced Nrf2 upregulation readily activates pDNAiNOS to express excessive iNOS, which then depletes CSC-intrinsic arginine while generating abundant nitric oxide (NO) for in-situ amplification of LDR-mediated cytotoxicity. Meanwhile, LDR also upregulates NQO1 expression to promote LAP-mediated ROS generation. These effects could act in a cooperative manner to potently damage CSC mitochondria, which not only blocks OXPHOS activity to drive the differentiation of CSCs for abolishing their self-renewal and resistance capability, but also enhances their propensity towards immunogenic necroptosis to elicit adaptive antitumor immunity, showing significant potential for treating therapy-persistent tumors.

Recurrence of breast cancer may be due to the presence of breast cancer stem cells (BCSC). Abnormal tumor cell growth is closely associated with increased reactive oxygen species (ROS) and disruption of redox homeostasis, and BCSCs exhibit low levels of ROS. The detailed mechanism between the low levels of ROS in BCSCs and their maintenance of stemness characteristics has not been reported. A growing number of studies have shown that tumor development is often accompanied by metabolic reprogramming, which is an important hallmark of tumor cells. As the first rate-limiting enzyme of pentose phosphate pathway (PPP), the expression of G6PD is precisely regulated in tumor cells, and there is a certain correlation between PPP and BCSCs. MiR-375 has been shown to inhibit stem cell-like properties in breast cancer, but the exact mechanism is not clear. Here, KLF5, as a transcription factor, was identified to bind to the promoter of G6PD to promote its expression, whereas miR-375 inhibited the expression of KLF5 by binding to the 3'UTR region of KLF5 mRNA and thus reduced the expression of G6PD expression, inhibits PPP to reduce NADPH, and increases ROS levels in breast cancer cells, thereby weakening breast cancer cell stemness. Our study reveals the specific mechanism by which miR-375 targets the KLF5/G6PD signaling axis to diminish the stemness of breast cancer cells, providing a therapeutic strategy against BCSCs.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with a high mortality rate and exhibits a limited response to apoptosis-dependent chemotherapeutic drugs (e.g., gemcitabine, Gem). This is mainly attributed to the antioxidant defense system (glutathione and aldehyde dehydrogenase (ALDH) 1A1), which sustains stemness features of cancer stem cells (CSCs) and activated pancreatic stellate cells (PSCs)-generated excess stromal proteins. This dense stroma retards drug delivery.

This study established co-spheroid model consisting of mouse PDAC cell line (KPC) and PSCs (1:5) to accurately investigate the anti-PDAC activity of nanocomplex of ferrous oxide nanoparticles-diethyldithiocarbamate (FeO NPs-DE), compared to Gem, using in vitro and in vivo 3D models.

In vitro and in vivo co-spheroid models demonstrated higher therapeutic efficacy of FeO NPs-DE than Gem. FeO NPs-DE induced selective accumulation of iron-dependent ferroptosis (non-apoptosis)-generated a lethal lipid peroxidation that was potentiated by DE-mediated glutathione and ALDH1A1 suppression. This led to collapse of stemness, as evidenced by down-regulating CSC genes and p-AKT protein expression. Subsequently, gene and/or protein levels of PSC activators (transforming growth factor (TGF)-β, plasminogen activator inhibitor-1, ZEB1, and phosphorylated extracellular signal-regulated kinase) and stromal proteins (collagen 1A2, smooth muscle actin, fibronectin, and matrix metalloproteinase-9) were suppressed. Moreover, DE of nanocomplex enhanced caspase 3-dependent apoptosis with diminishing the main oncogene, BCL-2.

FeO NPs-DE had a stronger eradicating effect than Gem on primary and metastatic peritoneal PDAC tumors. This nanocomplex-mediated ferroptosis and stemness inhibition provides an effective therapeutic approach for PDAC.

Oncolytic virotherapy has emerged as a promising strategy for cancer treatment by selectively targeting and lysing tumor cells. However, its efficacy is often limited in certain tumor types due to multiple factors. This study explores the combination of oncolytic adenoviruses with Erastin, a potent ferroptosis inducer, to enhance antitumor efficacy in oncolytic virus-insensitive cancer cell lines. In vitro experiments demonstrated that Erastin significantly increased the cytotoxicity of oncolytic virotherapy, leading to greater inhibition of cell proliferation and elevated rates of cell death compared to monotherapies. The combination treatment further promoted ferroptosis, as evidenced by increased reactive oxygen species (ROS) levels, enhanced lipid peroxidation, and disrupted redox homeostasis. RNA sequencing identified the downregulation of Dickkopf-1 (DKK1) as a key mediator of the enhanced ferroptotic effect. Restoring the expression of DKK1 partially mitigated the cytotoxic effects of the combination therapy, highlighting its crucial role in mediating the enhanced ferroptosis-induced oncolytic virotherapy efficacy. In vivo studies further validated these findings, demonstrating that the combined treatment significantly reduced tumor growth without inducing notable toxicity. This novel therapeutic approach has great potential to enhance the efficacy of oncolytic virotherapy in cancers resistant to oncolytic viruses by inducing ferroptosis. Further investigation in clinically relevant models is warranted to fully elucidate the underlying mechanisms and to optimize this combination strategy for potential clinical applications.

Gastric cancer (GC) is a frequently diagnosed malignant tumor in clinical settings; however, the mechanisms underlying its tumorigenesis remain inadequately understood. In this study, we identified significantly elevated expression levels of AKR1B1 in GC tissues through quantitative polymerase chain reaction (qPCR) and western blotting assays. Furthermore, a negative correlation was established between patient survival probability and AKR1B1 expression levels. Functionally, our experiments, including colony formation, transwell migration, and xenograft assays, demonstrated that the depletion of AKR1B1 inhibited the proliferation and progression of GC cells both in vivo and in vitro. Additionally, the assessment of reactive oxygen species (ROS), malondialdehyde (MDA), glutathione (GSH), and mitochondrial morphology confirmed that AKR1B1 depletion induces ferroptosis. Mechanistically, we found that AKR1B1 interacts with STAT3, which subsequently activates SLC7A11. Notably, the ferroptosis induced by AKR1B1 depletion could be reversed by the overexpression of SLC7A11, thereby substantiating these interactions. In conclusion, our findings identify AKR1B1 as a novel oncogene in GC and elucidate the mechanism involving the AKR1B1-STAT3-SLC7A11 pathway and ferroptosis, providing new insights for potential therapeutic strategies in the treatment of GC.

The acidic tumor microenvironment (TME) favors cancer aggressiveness via incompletely understood pathways. Here, we asked whether adaptation to environmental acidosis (pH 6.5) selects for human pancreatic cancer stem cell (CSC) properties. RNA sequencing (RNA-seq) of acid-adapted (AA) Panc-1 cells revealed CSC pathway enrichment and upregulation of CSC markers. AA Panc-1 cells exhibited classical CSC characteristics including increased aldehyde dehydrogenase (ALDH) activity and β-catenin activity. Panc-1, PaTu8988s, and MiaPaCa-2 cells all exhibited increased pancreatosphere-forming efficiency after acid adaptation but differed in CSC marker expression and did not exhibit typical flow cytometric CSC populations. However, single-nucleus sequencing revealed the acid adaptation-induced emergence of Panc-1 cell subpopulations with clear CSC characteristics. In orthotopic mouse tumors, AA Panc-1 cells exhibited enhanced aggressiveness, liver and lung metastasis, compared to controls. Collectively, our work suggests that acid adaptation enriches for pancreatic CSC phenotypes with unusual traits via several trajectories, providing new insight into how acidic microenvironments favor cancer aggressiveness.

Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, plays a pivotal role in various physiological and pathological processes. In this review, we summarize the core mechanisms of ferroptosis, emphasizing its intricate connections to lipid metabolism, including fatty acid synthesis, phospholipid remodeling, and oxidation dynamics. We further highlight advancements in detection technologies, such as fluorescence imaging, lipidomics, and in vivo PET imaging, which have deepened our understanding of ferroptotic regulation. Additionally, we discuss the role of ferroptosis in human diseases, where it acts as a double-edged sword, contributing to cancer cell death while also driving ischemia-reperfusion injury and neurodegeneration. Finally, we explore therapeutic strategies aimed at either inducing or inhibiting ferroptosis, including iron chelation, antioxidant modulation, and lipid-targeted interventions. By integrating mechanistic insights, disease relevance, and therapeutic potential, this review provides a comprehensive perspective on ferroptosis as a crucial interface between lipid metabolism and oxidative stress.

In recent 10 years, ferroptosis has become a hot research direction in the scientific research community as a new way of cell death. Iron toxicity accumulation and lipotoxicity are unique features. Several studies have found that ferroptosis is involved in the regulation of the hepatic microenvironment and various hepatic metabolisms, thereby mediating the progression of related liver diseases. For example, NRF2 and FSP1, as important regulatory proteins of ferroptosis, are involved in the development of liver tumors and liver failure. In this manuscript, we present the mechanisms involved in ferroptosis, the concern of ferroptosis with the liver microenvironment and the progression of ferroptosis in various liver diseases. In addition, we summarize recent clinical advances in targeted ferroptosis therapy for related diseases. We expect that this manuscript can provide a new perspective for clinical treatment of related diseases.

Persistence of drug-resistant breast cancer stem cells (brCSCs) after a chemotherapeutic regime correlates with disease recurrence and elevated mortality. Therefore, deciphering mechanisms that dictate their drug-resistant phenotype is imperative for designing targeted and more effective therapeutic strategies. The transcription factor SOX2 has been recognized as a protagonist in brCSC maintenance, and previous studies have confirmed that inhibition of SOX2 purportedly eliminated these brCSCs. However, pharmacological targeting of transcription factors like SOX2 is challenging due to their structural incongruities and intrinsic disorders in their binding interfaces. Therefore, transcriptional co-activators may serve as a feasible alternative for effectively targeting the brCSCs. Incidentally, transcriptional co-activators YAP/TAZ were found to be upregulated in CD44+/CD24-/ALDH+ cells isolated from patient breast tumors and CSC-enriched mammospheres. Interestingly, it was observed that YAP/TAZ exhibited direct physical interaction with SOX2 and silencing YAP/TAZ attenuated SOX2 expression in mammospheres, leading to significantly reduced sphere forming efficiency and cell viability. YAP/TAZ additionally manipulated redox homeostasis and regulated mitochondrial dynamics by restraining the expression of the mitochondrial fission marker, DRP1. Furthermore, YAP/TAZ inhibition induced DRP1 expression and impaired OXPHOS, consequently inducing apoptosis in mammospheres. In order to enhance clinical relevance of the study, an FDA-approved drug verteporfin (VP), was used for pharmacological inhibition of YAP/TAZ. Surprisingly, VP administration was found to reduce tumor-initiating capacity of the mammospheres, concomitant with disrupted mitochondrial homeostasis and significantly reduced brCSC population. Therefore, VP holds immense potential for repurposing and decisively eliminating the chemoresistant brCSCs, offering a potent strategy for managing tumor recurrence effectively.

Breast cancer, characterized by unique epidemiological patterns and significant heterogeneity, remains one of the leading causes of malignancy-related deaths in women. The increasingly nuanced molecular subtypes of breast cancer have enhanced the comprehension and precision treatment of this disease. The mechanisms of tumorigenesis and progression of breast cancer have been central to scientific research, with investigations spanning various perspectives such as tumor stemness, intra-tumoral microbiota, and circadian rhythms. Technological advancements, particularly those integrated with artificial intelligence, have significantly improved the accuracy of breast cancer detection and diagnosis. The emergence of novel therapeutic concepts and drugs represents a paradigm shift towards personalized medicine. Evidence suggests that optimal diagnosis and treatment models tailored to individual patient risk and expected subtypes are crucial, supporting the era of precision oncology for breast cancer. Despite the rapid advancements in oncology and the increasing emphasis on the clinical precision treatment of breast cancer, a comprehensive update and summary of the panoramic knowledge related to this disease are needed. In this review, we provide a thorough overview of the global status of breast cancer, including its epidemiology, risk factors, pathophysiology, and molecular subtyping. Additionally, we elaborate on the latest research into mechanisms contributing to breast cancer progression, emerging treatment strategies, and long-term patient management. This review offers valuable insights into the latest advancements in Breast Cancer Research, thereby facilitating future progress in both basic research and clinical application.

Wnt-induced signaling protein 1 (WISP1) and Dickkopf-1 (DKK1) are highly expressed in esophageal squamous cell carcinoma (ESCC), but no direct connection was identified between them. Phenotypic plasticity is a hallmark of ESCC. This research intended to identify the association between WISP1 and DKK1 and their roles in the phenotypic plasticity of ESCC.

Genes differentially expressed in esophageal carcinoma were analyzed in the GEO database, followed by analyses of GO and KEGG enrichment to screen the hub gene. WISP1 expression and DKK1 secretion was assessed in ESCC tissues and cells. The tumor xenograft and in vivo metastasis models were established by injecting ESCC cells into nude mice. Functional deficiency and rescue experiments were conducted, followed by assays for cell proliferation, migration/invasion, stemness, epithelial-mesenchymal transition (EMT), and apoptosis, as well as tumor volume, weight, proliferation, stemness, and lung metastasis. The binding relationship and co-expression of WISP1 and DKK1 were determined.

WISP1 and DKK1 were upregulated in ESCC cells and tissues, and WISP1 was enriched in the cell stemness and Wnt pathways. WISP1 knockdown subdued proliferation, migration/invasion, EMT activity, and stemness but enhanced apoptosis in ESCC cells. WISP1 knockdown restrained ESCC growth, proliferation, stemness, and metastasis in vivo. WISP1 bound to DKK1 in ESCC. DKK1 overexpression abolished the repressive impacts of WISP1 knockdown on the malignant behaviors of ESCC cells in vitro and of ESCC tumor in vivo.

Knockdown of WISP1/DKK1 restrains the phenotypic plasticity in esophageal squamous cell carcinoma by suppressing epithelial-mesenchymal transition and stemness.

Although tamoxifen is commonly utilized as adjuvant therapy for Estrogen Receptor alpha (ERα)-positive breast cancer patients, approximately 30-50% of individuals treated with tamoxifen experience relapse. Therefore, it is essential to investigate additional factors besides ERα that influence the estrogen response. In this study, cross-analysis of databases were performed, and the results revealed a significant association between LINC00626 and ERα signaling as well as increased expression levels of this gene in tamoxifen-resistant cells. LINC00626 is a novel ERα-regulated long non-coding RNA (lncRNA) that has not yet been examined for its potential contribution to endocrine therapy resistance. This study revealed that the upregulation of LINC00626 in breast cancer was associated with poor overall survival in patients. Additionally, ERα signaling was found to transcriptionally regulate LINC00626 expression, thereby promoting cancer progression and enhancing resistance to tamoxifen in breast cancer cells via the regulation of UPF1 expression. Depletion of LINC00626 restored sensitivity to tamoxifen by activating the PERK-ATF4-CHOP signaling pathway via UPF1. These findings support the role of LINC00626 as a potential therapeutic target for combating tamoxifen resistance.

Breast cancer is the most prevalent malignancy among women worldwide, with breast cancer stem cells (BCSCs) being the primary drivers of metastasis and recurrence. Numerous studies have elucidated the relationship between ferroptosis and cellular stemness, identifying the Xc- system as a key regulatory mechanism governing ferroptosis. However, the interplay between CAV1 and ferroptosis, along with its implications for stemness in breast cancer, remains inadequately understood. This gap in knowledge impedes advancements in targeted therapies for breast cancer. We employed immunohistochemistry and bioinformatics analyses to demonstrate the downregulation of CAV1 in breast cancer tissues. Additionally, we utilized CCK-8 assays, EDU staining, and Transwell assays to assess cell proliferation, migration, and invasion capabilities. Furthermore, we evaluated indicators associated with ferroptosis while examining markers related to stemness through sphere culture experiments and flow cytometry techniques. Our findings indicate that CAV1 expression can induce cell death via ferroptosis while simultaneously inhibiting both cell proliferation and features of stemness by upregulating IFNGR1 and promoting ferroptosis. Moreover, our in vivo experiments revealed that overexpression of CAV1 enhances the efficacy of anti-PD-1 therapy. In conclusion, our study elucidates the regulatory role of CAV1 on ferroptosis within breast cancer contexts; it suppresses BCSC characteristics while positioning CAV1 as a promising therapeutic target for combating this disease.

H3K27ac has been widely recognized as a representative epigenetic marker of active enhancer, while its regulatory mechanisms in pathogenesis of metabolic dysfunction-associated steatotic liver disease (MASLD) remain elusive. Here, a genome-wide comparative study on H3K27ac activities and transcriptome profiling in high fat diet (HFD)-induced MASLD model is performed. A significantly enhanced H3K27ac density with abundant alterations of regulatory transcriptome is observed in MASLD rats. Based on integrative analysis of ChIP-Seq and RNA-Seq, TDO2 is identified as a critical contributor for abnormal lipid accumulation, transcriptionally activated by YY1-promoted H3K27ac. Furthermore, TDO2 depletion effectively protects against hepatic steatosis. In terms of mechanisms, TDO2 activates NF-κB pathway to promote macrophages M1 polarization, representing a crucial event in MASLD progression. A bovine serum albumin nanoparticle is fabricated to provide sustained release of Allopurinol (NPs-Allo) for TDO2 inhibition, possessing excellent biocompatibility and desired targeting capacity. Venous injection of NPs-Allo robustly alleviates HFD-induced metabolic disorders. This study reveals the pivotal role of TDO2 and its underlying mechanisms in pathogenesis of MASLD epigenetically and genetically. Targeting H3K27ac-TDO2-NF-κB axis may provide new insights into the pathogenesis of abnormal lipid accumulation and pave the way for developing novel strategies for MASLD prevention and treatment.

Disulfidptosis, a newly identified form of regulated cell death associated with disruption of disulfide bond formation in the endoplasmic reticulum, involves the dysregulation of disulfidptosis-related genes (DRGs) that may contribute to cancer development and progression. However, the molecular mechanisms and clinical implications of DRGs in different cancer types remain poorly characterized. Therefore, in this comprehensive study, we investigated the expression, prognostic value, and functional roles of four recently identified DRGs (SLC7A11, SLC3A2, RPN1, and NCKAP1) across various cancers. Especially, in clinical samples of glioblastoma, we found that RPN1 was significantly correlated with patient survival. Through mutation landscape analysis, we identified diverse missense mutations in these DRGs, with NCKAP1 exhibiting the highest mutation frequency (5.9% in skin cutaneous melanoma). Additionally, we observed positive correlations between these DRGs and tumor stemness (DNAss DNA stemness score and RNAss RNA stemness score) as well as RNA modifications, particularly m6A modification, in several cancer types. Furthermore, high expression of SLC7A11, RPN1, and NCKAP1 was positively associated with infiltration of T-helper type 2 (Th2) cells in various cancers, while high expression of SLC7A11, SLC3A2, and RPN1 correlated with tumor mutational burden (TMB) in 10, 4, and 8 tumor types, respectively. Utilizing a protein-protein interaction network, we identified the RHO GTPases Activate WASPs and WAVEs pathway as significantly enriched, suggesting the involvement of these DRGs in cancer-related signaling pathways. Collectively, our findings provide novel insights into the molecular mechanisms and clinical implications of DRGs in pan-cancer, highlighting their potential as biomarkers and therapeutic targets for cancer treatment.

Farnesoid X receptor (NR1H4/FXR) functions as a scavenger of lipid peroxide products and drives the proliferation and metastasis of various cancers. However, the underlying molecular mechanisms remain poorly understood. In our study, we found that the expression levels of FXR, vimentin and SLC7A11 were significantly higher in breast cancer tissues, particularly in metastatic cancer tissues compared to non-metastatic ones. Furthermore, the increased FXR expression was positively correlated with vimentin and SLC7A11 in clinical tumor specimens. In addition, a high level of FXR correlated with poor prognosis in patients with breast cancer. Both Z-Guggulsterone (Z-GS), as a pharmacological inhibitor of FXR, and silencing FXR curbed proliferation and migration of breast cancer cells by promoting ferroptosis. Notably, our results showed that FXR competitively bound to CREB-binding protein (CBP) to suppress the interaction between p53 and CBP in the nucleus, and thus prevented p53 acetylation at lys382, which was essential for upregulating the expression of SLC7A11. Conversely, FXR knockdown increased the interaction between p53 and CBP and promoted p53 acetylation, which ultimately led to facilitating ferroptosis in breast cancer cells. More importantly, we also found that Z-GS inhibited TGF-β1-induced tumor growth and metastasis of breast cancer primarily through ferroptosis via regulating CBP-dependent p53 acetylation in nude mice. In conclusion, the FXR was first reported as a tumor promoter that enhanced the proliferation and metastasis of breast cancer cells through regulating CBP-dependent p53 K382 acetylation. It proposes that FXR may serve as a potential therapeutic target for the treatment of breast cancer.

Intra-tumor immune infiltration plays a pivotal role in the interaction with tumor cells in hepatocellular carcinoma (HCC). However, its phenotype and related spatial structure remained elusive. To address these limitations, we conducted a comprehensive study combining spatial data (38,191 spots from eight samples) and single-cell data (56,022 cells from 20 samples). Our analysis revealed two distinct infiltration patterns: immune exclusion and immune activation. Plasma cells emerged as the primary cell type within intra-tumor immune clusters. Notably, we observed the co-location of CCL19+ fibroblasts with plasma cells, which secrete chemokines and promote T-cell activation and leukocyte migration. Conversely, in immune-exclusion samples, this co-location was primarily observed in the adjacent normal area. This co-localization correlated with T cell infiltration and the formation of tertiary lymphoid structures, validated by multiplex immunofluorescence conducted on twenty HCC samples. Both CCL19+ fibroblasts and plasma cells were associated with favorable survival outcomes. In an immunotherapy cohort, HCC patients who responded favorably exhibited higher infiltration of CCL19+ fibroblasts and plasma cells. Additionally, we observed the accumulation of DKK1+ tumor cells within the tumor area in immune-exclusion samples, particularly at the tumor boundary, which inhibited the infiltration of CCL19+ fibroblasts and plasma cells into the tumor area. Furthermore, in immune-exclusion samples, the SPP1 signaling pathway demonstrated the highest activity in communication between tumor and immune clusters, and CCL19-CCR7 played a pivotal role in the self-communication of immune clusters. This study elucidates immune exclusion and immune activation patterns in HCC and identifies relevant factors contributing to immune resistance.

Human ALDH comprise 19 subfamilies in which ALDH1A1, ALDH1A3, ALDH3A1, ALDH5A1, ALDH7A1, and ALDH18A1 are implicated in CSC. Studies have shown that ALDH can also be involved in drug resistance and standard chemotherapy regimens are ineffective in treating patients at the stage of disease recurrence. Existing chemotherapeutic drugs eliminate the bulk of tumors but are usually not effective against CSC which express ALDH+ population. Henceforth, targeting ALDH is convincing to treat the patient's post-relapse. Combination therapies that interlink signaling mechanisms seem promising to increase the overall disease-free survival rate. Therefore, targeting ALDH through ALDH inhibitors along with immunotherapies may create a novel platform for translational research. This review aims to fill in the gap between ALDH1 family members in relation to its cell signaling mechanisms, highlighting their potential as molecular targets to sensitize recurrent tumors and bring forward the future development concerning the current progress and draw backs. This review summarizes the role of cancer stem cells and their upregulation by maintaining the tumor microenvironment in which ALDH is specifically highlighted. It discusses the regulation of ALDH family proteins and the crosstalk between ALDH and CSC in relation to cancer metabolism. Furthermore, it establishes the correlation between ALDH involved signaling mechanisms and their specific targeted inhibitors, as well as their functional modularity, bioavailability, and mechanistic role in various cancers.

Cancer therapeutic resistance as a common hallmark of cancer is often responsible for treatment failure and poor patient survival. Cancer stem-like cells (CSCs) are one of the main contributors to therapeutic resistance, cancer relapse and metastasis. Through screening from our in-house library of natural products, we found polyphyllin II (PPII) as a potent anti-CSC compound for triple-negative breast cancer (TNBC). To enhance anti-CSC selectivity and improve druggability of PPII, we leverage the liposome-mediated delivery technique for increasing solubility of PPII, and more significantly, attaining broader therapeutic window. Liposomal PPII demonstrates its marked potency to inhibit tumor growth, post-surgical recurrence and metastasis compared to commercial liposomal chemotherapeutics in the mouse models of CSC-enriched TNBC tumor. We further identify PPII as an inhibitor of the Ras-related nuclear (RAN) protein whose upregulated expression is correlated with poor clinical outcomes. The direct binding of PPII to RAN reduces TNBC stemness, thereby suppressing tumor progression. Our work offers a significance from drug discovery to drug delivery benefiting from liposome technique for targeted treatment of high-stemness tumor.

Tumor metastasis is a major threat to cancer patient survival. The organ-specific niche plays a pivotal role in tumor organotropic metastasis. Fibroblasts serve as a vital component of the metastatic microenvironment, but how heterogeneous metastasis-associated fibroblasts (MAFs) promote organotropic metastasis is poorly characterized. Here, we aimed to decipher the heterogeneity of MAFs and elucidate the distinct roles of these fibroblasts in pulmonary metastasis formation in breast cancer.

Mouse models of breast cancer pulmonary metastasis were established using an in vivo selection method of repeated injections of metastatic cells purified from the mouse lung. Single-cell RNA-sequencing (scRNA-seq) was employed to investigate the heterogeneity of MAFs. Transgenic mice were used to examine the contribution of tryptophan 2,3-dioxygenase-positive matrix fibroblasts (TDO2+ MFs) in lung metastasis.

We uncovered 3 subtypes of MAFs in the lung metastatic microenvironment, and their transcriptome profiles changed dynamically as lung metastasis evolved. As the predominant subtype, MFs were exclusively marked by platelet-derived growth factor receptor alpha (PDGFRA) and mainly located on the edge of the metastasis, and T cells were enriched around MFs. Notably, high MF signatures were significantly associated with poor survival in breast cancer patients. Lung metastases were markedly diminished, and the suppression of T cells was dramatically attenuated in MF-depleted experimental metastatic mouse models. We found that TDO2+ MFs controlled pulmonary metastasis by producing kynurenine (KYN), which upregulated ferritin heavy chain 1 (FTH1) level in disseminated tumor cells (DTCs), enabling DTCs to resist ferroptosis. Moreover, TDO2+ MF-secreted chemokines C-C motif chemokine ligand 8 (CCL8) and C-C motif chemokine ligand 11 (CCL11) recruited T cells. TDO2+ MF-derived KYN induced T cell dysfunction. Conditional knockout of Tdo2 in MFs diminished lung metastasis and enhanced immune activation.

Our study reveals crucial roles of TDO2+ MFs in promoting lung metastasis and DTCs' immune evasion in the metastatic niche. It suggests that targeting the metabolism of lung-specific stromal cells may be an effective treatment strategy for breast cancer patients with lung metastasis.

A cell membrane-derived vesicle (MV) that has cell-mimicking features with characteristic functionalities holds vast appeal for biomimetic nanomedicine and drug delivery but suffers from a major limitation of innate fragility and poor stability. Herein, we report a lipid-anchoring strategy for stabilizing MV for enhanced drug delivery. An array of amphiphilic mono-acyl phosphatidylcholines (MPCs) with specific hydrophobic moieties are synthesized and readily engineered on MV based on their commendable aqueous solubility and efficient membrane insertability. Incorporation of MPCs containing rigid ring structures in the hydrophobic segment demonstrates the potency of stabilizing MV by the combined ordering and condensing effects. The optimized MPC-stabilized MV exhibits prolonged circulation in the bloodstream, elevated accumulation within a tumor, and enhanced therapeutic effects of chemotherapeutic and photothermal drugs. Moreover, doxorubicin-loaded MV, engineered with mono-all-trans retinoyl phosphatidylcholine as an MV stabilizer and a therapeutic prodrug, potently suppresses growth and metastasis of high-stemness tumors.

Radiofrequency ablation (RFA) is one of the most common minimally invasive techniques for the treatment of solid tumors, but residual malignant tissues or small satellite lesions after insufficient RFA (iRFA) are difficult to remove, often leading to metastasis and recurrence. Here, Fe-TPZ nanoparticles are designed by metal ion and (TPZ) ligand complexation for synergistic enhancement of RFA residual tumor therapy. Fe-TPZ nanoparticles are cleaved in the acidic microenvironment of the tumor to generate Fe2+ and TPZ. TPZ, an anoxia-dependent drug, is activated in residual tumors and generates free radicals to cause tumor cell death. Elevated Fe2+ undergoes a redox reaction with glutathione (GSH), inducing a strong Fenton effect and promoting the production of the highly toxic hydroxyl radical (•OH). In addition, the ROS/GSH imbalance induced by this treatment promotes immunogenic cell death (ICD), which triggers the release of damage-associated molecular patterns, macrophage polarization, and lymphocyte infiltration, thus triggering a systemic antitumor immune response and noteworthy prevention of tumor metastasis. Overall, this integrated treatment program driven by multiple microenvironment-dependent pathways overcomes the limitations of the RFA monotherapy approach and thus improves tumor prognosis. Furthermore, these findings aim to provide new research ideas for regulating the tumor immune microenvironment.

Gastric cancer stem cells (GCSCs) play crucial role in the development, recurrence, and resistance of gastric cancer (GC). Cinobufacini, a traditional Chinese medicine, offers significant advantages in improving tumor therapy. However, pre-clinical investigation into the antitumor effect and mechanism of Cinobufacini on GC is still lacking. Additionally, it has not been reported whether Cinobufacini is related to cancer stem cells (CSCs).

The CCK-8, clone formation, EdU staining, transwell and wound healing experiments were performed to assess the cell toxicity of Cinobufacini and demonstrate the preventive effects of Cinobufacini on proliferation, invasion, and migration of GC cells. Elucidating the underlying mechanism of Cinobufacini in GC based on the transcriptome sequencing. Flow cytometry assays, sphere formation assays, subcutaneous xenograft model in nude mice, and immunofluorescent staining have been used to investigate whether the anti-GC effect of Cinobufacini is associated with GCSCs and enhancing therapeutic response to 5-Fluorouracil (5-FU).

Cinobufacini exerts minimal impact on normal human gastric epithelium cell GES-1, while significantly suppressing the proliferation, invasion, and migration of GC cell lines. Additionally, Cinobufacini attenuates the stemness of GCSCs by disrupting the AKT/GSK-3β/β-catenin signaling cascade. Moreover, Cinobufacin enhances the anti-tumor effects of 5-FU against GCSCs by reducing in vitro sphere formation and inhibiting subcutaneous graft tumor growth in vivo.

Cinobufacini enhances the therapeutic response of 5-FU against GC by targeting CSCs via AKT/GSK-3β/β-catenin signaling axis. Our findings offer a crucial insight into the molecular mechanism of Cinobufacini's anticancer activity in GC.

A novel series of 1,8-naphthalimide piperazinamide based benzenesulfonamides derivatives were designed and synthesized as carbonic anhydrase IX (CA IX) inhibitors and ferroptosis inducers for the treatment of triple-negative breast cancer (TNBC). The representative compound 9o exhibited more potent inhibitory activity and selective against CA IX over off-target CA II, compared with positive control SLC-0111. Molecular docking study was also performed to gain insights into the binding interactions of 9o in the binding pocket of CAIX. Moreover, compound 9o exhibited superior antitumor activities against breast cancer cells under hypoxia than that of normoxia conditions. Mechanism studies revealed that compound 9o could act as DNA intercalator and effectively suppressed cell migration, arrested the cell cycle at G1/S phase and induced apoptosis in MDA-MB-231 cells, while inducing ferroptosis accompanied by the dissipation of MMP and the elevation intracellular levels of ROS. Notably, in vivo studies demonstrated that 9o effectively inhibited tumor growth and metastasis in a highly metastatic murine breast cancer 4 T1 xenograft model. Taken together, this study suggests that compound 9o represents a potent and selective CA IX inhibitor and ferroptosis inducer for the treatment of TNBC.

Glutathione (GSH), the main cellular antioxidant, dynamically influences tumor growth, metastasis, and resistance to therapy in the tumor microenvironment (TME), which comprises cancer cells, immune cells, stromal cells, and non-cellular components, including the extracellular matrix, metabolites, hypoxia, and acidity. Cancer stem cells (CSCs) and T cells are minor but significant cell subsets of the TME. GSH dynamics influences the fate of CSCs and T cells. Here, we explored GSH dynamics in CSCs and T cells within the TME, as well as therapeutic approaches that could target these dynamics.

Data published in 2020 by the International Agency for Research on Cancer (IARC) of the World Health Organization show that breast cancer (BC) has become the most common cancer globally, affecting more than 2 million women each year. The complex tumor microenvironment, drug resistance, metastasis, and poor prognosis constitute the primary challenges in the current diagnosis and treatment of BC. Magnetic iron oxide nanoparticles (MIONPs) have emerged as a promising nanoplatform for diagnostic tumor imaging as well as therapeutic drug-targeted delivery due to their unique physicochemical properties. The extensive surface engineering has given rise to multifunctionalized MIONPs. In this review, the latest advancements in surface modification strategies of MIONPs over the past five years are summarized and categorized as constrast agents and drug delivery platforms. Additionally, the remaining challenges and future prospects of MIONPs-based targeted delivery are discussed.

The unique "Iron Addiction" feature of cancer stem cells (CSCs) with tumorigenicity and plasticity generally contributes to the tumor recurrence and metastasis after a lumpectomy. Herein, a novel "Ferroptosis Amplification" strategy is developed based on integrating gallic acid-modified FeOOH (GFP) and gallocyanine into Pluronic F-127 (F127) and carboxylated chitosan (CC)-based hydrogel for CSCs eradication. This "Ferroptosis Amplifier" hydrogel is thermally sensitive and achieves rapid gelation at the postsurgical wound in a breast tumor model. Specifically, gallocyanine, as the Dickkopf-1 (DKK1) inhibitor, can decrease the expression of SLC7A11 and GPX4 and synergistically induce ferroptosis of CSCs with GFP. Encouragingly, it is found that this combination suppresses the migratory and invasive capability of cancer cells via the downregulation of matrix metalloproteinase 7 (MMP7). The in vivo results further confirm that this "Ferroptosis Amplification" strategy is efficient in preventing tumor relapse and lung metastasis, manifesting an effective and promising postsurgical treatment for breast cancer.

The glycans form a unique complex on the surface of cancer cells and play a pivotal role in tumor progression, impacting proliferation, invasion, and metastasis. TRA-1-60 is a glycan that was identified as a critical marker for the establishment of fully reprogrammed inducible pluripotent stem cells. Its expression has been detected in multiple cancer tissues, including embryonal carcinoma, prostate cancer, and pancreatic cancer, but the biological and pathological characterization of TRA-1-60-expressing tumor cells remains unclear within various types of malignancies. Here, we report the biological characteristics of TRA-1-60-expressing gastric cancer cells, especially those with its cell surface expression, and the therapeutic significance of targeting TRA-1-60. The cells with cell membrane expression of TRA-1-60 were mainly observed in the invasive area of patient gastric cancer tissues and correlated with advanced stages of the disease based on histopathological and clinicopathological analyses. In vitro analysis using a scirrhous gastric adenocarcinoma line, HSC-58, which highly expresses TRA-1-60 on its plasma membrane, revealed increased stress-resistant mechanisms, supported by the upregulation of glutathione synthetase and NCF-1 (p47phox) via lipid-ROS regulatory pathways, as detected by RNA-seq analysis followed by oxidative stress gene profiling. Our in vivo therapeutic study using the TRA-1-60-targeting antibody-drug conjugate, namely, Bstrongomab-conjugated monomethyl auristatin E, showed robust efficacy in a mouse model of peritoneal carcinomatosis induced by intraperitoneal xenograft of HSC-58, by markedly reducing massive tumor ascites. Thus, targeting the specific cell surface glycan, TRA-1-60, shows a significant therapeutic impact in advanced-stage gastric cancers.

Neuroimmune and neurodegenerative ailments impose a substantial societal burden. Neuroimmune disorders involve the intricate regulatory interactions between the immune system and the central nervous system. Prominent examples of neuroimmune disorders encompass multiple sclerosis and neuromyelitis optica. Neurodegenerative diseases result from neuronal degeneration or demyelination in the brain or spinal cord, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. The precise underlying pathogenesis of these conditions remains incompletely understood. Ferroptosis, a programmed form of cell death characterised by lipid peroxidation and iron overload, plays a pivotal role in neuroimmune and neurodegenerative diseases. In this review, we provide a detailed overview of ferroptosis, its mechanisms, pathways, and regulation during the progression of neuroimmune and neurodegenerative diseases. Furthermore, we summarise the impact of ferroptosis on neuroimmune-related cells (T cells, B cells, neutrophils, and macrophages) and neural cells (glial cells and neurons). Finally, we explore the potential therapeutic implications of ferroptosis inhibitors in diverse neuroimmune and neurodegenerative diseases.

Polyamine metabolism and signaling play important roles in multiple cancers but have not previously been studied in Ewing sarcoma. Here, we show that blocking polyamine synthesis with D, L-alpha-difluoromethylornithine (DFMO) causes a G1 cell cycle arrest, dose-dependent decreases in sarcosphere formation from Ewing sarcoma cell lines growing in non-adherent conditions and a decrease in clonogenic growth in soft agar. Further, we utilized our orthotopic implantation/amputation model of Ewing sarcoma metastasis to demonstrate that DFMO slowed primary tumor growth in addition to limiting metastasis. RNA sequencing demonstrated gene expression patterns consistent with induction of ferroptosis caused by polyamine depletion. Induction of ferroptosis was validated in vitro by demonstrating that ferrostatin-1, an inhibitor of ferroptosis, allows sphere formation even in the presence of DFMO. Collectively, these results reveal a novel mechanism by which DFMO prevents metastasis - induction of ferroptosis due to polyamine depletion. Our results provide preclinical justification to test the ability of DFMO to prevent metastatic recurrence in Ewing sarcoma patients at high risk for relapse.

Breast cancer is the most frequently diagnosed malignancy and the second leading cause of cancer-related mortality among women worldwide. Recurrent metastasis is associated with poor patient outcomes and poses a significant challenge in breast cancer therapies. Cancer cells adapting to a new tissue microenvironment is the key event in distant metastasis development, where the disseminating tumor cells are likely to acquire genetic and epigenetic alterations during the process of metastatic colonization. Despite several decades of research in this field, the exact mechanisms governing metastasis are not fully understood. However, emerging body of evidence indicates that in addition to genetic changes, epigenetic reprogramming of cancer cells and the metastatic niche are paramount toward successful metastasis. Here, we review and discuss the latest knowledge about the salient attributes of metastasis and epigenetic regulation in breast cancer and crucial research domains that need further investigation.

Breast cancer in young patients is known to exhibit more aggressive biological behavior and is associated with a less favorable prognosis than the same disease in older patients, owing in part to an increased incidence of brain metastases. The mechanistic explanations behind these findings remain poorly understood. We recently reported that young mice, in comparison to older mice, developed significantly greater brain metastases in four mouse models of triple-negative and luminal B breast cancer. Here we have performed a quantitative mass spectrometry-based proteomic analysis to identify proteins potentially contributing to age-related disparities in the development of breast cancer brain metastases. Using a mouse hematogenous model of brain-tropic triple-negative breast cancer (MDA-MB-231BR), we harvested subpopulations of tumor metastases, the tumor-adjacent metastatic microenvironment, and uninvolved brain tissues via laser microdissection followed by quantitative proteomic analysis using high resolution mass spectrometry to characterize differentially abundant proteins potentially contributing to age-dependent rates of brain metastasis. Pathway analysis revealed significant alterations in signaling pathways, particularly in the metastatic microenvironment, modulating tumorigenesis, metabolic processes, inflammation, and neuronal signaling. Tenascin C (TNC) was significantly elevated in all laser microdissection (LMD) enriched compartments harvested from young mice relative to older hosts, which was validated and confirmed by immunoblot analysis of whole brain lysates. Additional in vitro studies including migration and wound-healing assays demonstrated TNC as a positive regulator of tumor cell migration. These results provide important new insights regarding microenvironmental factors, including TNC, as mechanisms contributing to the increased brain cancer metastatic phenotype observed in young breast cancer patients.

Cancer stem cells (CSCs), with their ability of self-renewal, unlimited proliferation, and multi-directional differentiation, contribute to tumorigenesis, metastasis, recurrence, and resistance to conventional therapy and immunotherapy. Eliminating CSCs has long been thought to prevent tumorigenesis. Although known to negatively impact tumor prognosis, research revealed the unexpected role of iron metabolism as a key regulator of CSCs. This review explores recent advances in iron metabolism in CSCs, conventional cancer therapies targeting iron biochemistry, therapeutic resistance in these cells, and potential treatment options that could overcome them. These findings provide important insights into therapeutic modalities against intractable cancers.

Ferroptosis is a type of regulated cell death characterized by iron accumulation and uncontrolled lipid peroxidation, leading to plasma membrane rupture and intracellular content release. Originally investigated as a targeted therapy for cancer cells carrying oncogenic RAS mutations, ferroptosis induction now exhibits potential to complement chemotherapy, immunotherapy, and radiotherapy in various cancer types. However, it can lead to side effects, including immune cell death, bone marrow impairment, liver and kidney damage, cachexia (severe weight loss and muscle wasting), and secondary tumorigenesis. In this review, we discuss the advantages and offer an overview of the diverse range of documented side effects. Furthermore, we examine the underlying mechanisms and explore potential strategies for side effect mitigation.