Phospholipids, complex lipids prevalent in the human body, play crucial roles in various pathophysiological processes. Beyond their synthesis and degradation, phospholipids can influence chemoresistance by participating in ferroptosis. Extensive evidence highlights the significant link between tumor drug resistance and phospholipids. Therefore, drugs targeting phospholipid metabolism itself or the synthesis of corresponding composite materials will effectively overcome the difficulties of clinical tumor treatment.

Ischemic stroke, a neurological condition with a complicated etiology that is accompanied by severe inflammation and oxidative stress, and ethanol (EtOH) may aggravate ischemia/reperfusion (I/R)-induced brain damage. However, the effect of prolonged alcohol intake on acute brain injury remains ambiguous. As part of the mitogen-activated protein kinase (MAPK) family, p38γ is involved in ferroptosis and inflammation in various diseases. This study explored how p38γ is involved in the effects of chronic EtOH consumption and brain injury caused by cerebral I/R. Brain damage was induced in the mice via the administration of a liquid alcohol-containing diet for 8 weeks, middle cerebral artery occlusion reperfusion (MCAO/R), or a combination of both. We verified that EtOH significantly exacerbated MCAO/R-induced brain damage, ferroptosis and inflammation. Notably, p38γ levels were increased in experimental mouse and cell models. p38γ knockdown markedly attenuated brain tissue damage, oxidative stress, and inflammatory cell infiltration in EtOH + MCAO/R-treated mice. Mechanistic experiments revealed that p38γ may regulate inflammation and ferroptosis through the p53/SLC7A11 pathway. Overall, our experimental results indicate that p38γ is crucial for regulating EtOH- and I/R-induced brain damage by modulating the p53/SLC7A11 pathway.

Gastrointestinal diseases are global health issues. Current drugs for gastrointestinal diseases cause discomfort and toxicity; consequently, the use of traditional medicines and their extracts has gained attention in recent years. Physochlaina physaloides (L) G. Don. (P. physaloides) is traditionally used for diarrhoea and gastroenteritis; however, its material basis and mechanism of action for gastric injury have not been fully studied.

This study aims to explore P. physaloides and their protective effects on gastric injury, together with the potential mechanisms.

We constructed chronic gastritis and gastric ulcer models in rats using 56 % ethanol and anhydrous ethanol, respectively. Additionally, we screened gastric injury pathways via transcriptomics and the gene expression omnibus (GEO) database. Subsequently, we constructed an ethanol-stimulated GES-1 cell model and screened the active fraction of P. physaloides based on the cell survival rate and antioxidant activity. The effect of the active fraction of P. physaloides was investigated via tissue structure (HE staining), mucus secretion (PAS staining), anti-inflammatory activity, antioxidant activity, and gastric acid secretion levels. We employed liquid chromatography-tandem mass spectrometry (LC-MS/MS) to determine the active components of P. physaloides and the drug components in blood, before investigating the mechanisms via immunofluorescence, transcriptomic, metabolomics, network pharmacology, molecular docking, qRT-PCR, western blotting, and flow cytometry.

The occurrence of gastritis, gastric ulcer, and gastric cancer is related to the PPAR/NF-κB signalling pathway, with decreased expression of FABP3 and PPARγ, and increased expression of Bcl-2 and TNF-α. The n-butanol fraction of P. physaloides (BPP) showed significant improvement in cell survival and antioxidant activity in vitro. BPP also alleviated inflammation and oxidative stress in rat models, including by upregulating CAT, GSH, SOD, IL-10, PGE2; downregulating VEGFA, IL-6, IL-8, TNF-α, and NO; improving pathological damage; restoring mucus levels; and reducing gastric acid secretion and macrophage expression. BPP and its active components, anisodamine and hyoscyamine, upregulated the expression of PPARα, PPARγ, CPT1, and FABP3, and downregulated NF-κB p65, thereby regulating the PPAR/NF-κB signalling pathway for gastroprotection. The BPP and its active components did not significantly increase the expression of GPX4 and SLC7A11, nor did they reduce the production of ROS. Therefore, their effects are unrelated to ferroptosis.

This study provides the first evidence of the effectiveness of BPP in the prevention of gastric ulcers and treatment of chronic gastritis. We adopted a multidisciplinary approach to demonstrate that BPP and its active components, anisodamine and hyoscyamine, protect against ethanol-induced gastric injury by regulating the PPAR/NF-κB and non-ferroptotic cell death pathways. BPP and its active components can target PPARγ and FABP3 and may have clinical application prospects to prevent gastric injury, which has unique advantages. These findings provide a scientific foundation for gastroprotection and expand the clinical applications of BPP.

Ovarian cancer represents a significant threat to women's health. and ferroptosis is recognized as a potential natural inhibitor in cancer therapy, the regulatory mechanism of TRIM25 in ovarian cancer and its potential for regulating ferroptosis as a treatment remain unclear.

The role of TRIM25 in ovarian cancer was examined through functional gain- and loss-of-function assays both in vitro and in vivo, while its target genes were identified. The stability and ubiquitination sites of PIEZO1 were analyzed using protein docking and ubiquitination experiments.

TRIM25 is highly expressed in ovarian cancer and promotes the growth and metastasis of ovarian cancer cells both in vivo and in vitro. Mechanistically, it facilitates PIEZO1 degradation through ubiquitination-dependent proteasome activity, inhibits ferroptosis, and stimulates ovarian cancer cell growth.

Our study clearly shows that TRIM25 stimulates ovarian cancer by inducing K63-linked ubiquitination of PIEZO1, which suppresses ferroptosis and promotes excessive proliferation of ovarian cancer cells. Further research identified the ubiquitination modification site on PIEZO1, providing insights for ovarian cancer treatment.

Triple-negative breast cancer (TNBC), an aggressive cancer with a high risk of metastasis and recurrence, is resistant to conventional chemotherapy. Ferroptosis, a non-apoptotic form of cell death, is primarily caused by excessive accumulation of lipid peroxides, and is closely associated with the occurrence and development of various diseases. Mounting evidence indicates that ferroptosis is becoming a promising treatment for TNBC based on its inherent characteristics. Herein, zwitterionic polymer poly (N-(3-sulfopropyl)-N-methacryloxyethyl-N,N-dimethylammonium betaine) (PSBMA)-coated gambogenic acid (GNA)-loaded magnetic composite nanoparticles (Fe3O4@PSBMA-GNA) were fabricated for chemotherapy combined with ferroptosis therapy for TNBC. Fe3O4@PSBMA-GNA achieved significant cytotoxicity against TNBC cell lines and contributed to the disruption of intracellular redox homeostasis. Furthermore, Fe3O4@PSBMA-GNA could induce apoptosis through the inhibition of Bcl-2 and trigger ferroptosis by inhibiting the PI3K/AKT/mTOR/GPX4 pathway in MDA-MB-231 cells simultaneously. Given the excellent blood circulation performance, Fe3O4@PSBMA-GNA enhanced tumor accumulation and showed a satisfactory tumor suppression effect on MDA-MB-231 tumor-bearing mice. This strategy of chemotherapy combined with ferroptosis therapy is expected to be a feasible treatment for refractory TNBC.

ObjectiveThis study aimed to examine the levels of solute carrier family seven number 11 (SLC7A11) and glutathione peroxidase 4 (GPX4) in the serum of patients with acute ischaemic stroke (AIS) and their relationship with disease severity.MethodsA total of 148 patients with AIS together with 148 healthy controls (HCs) were enrolled. The expression levels of SLC7A11 and GPX4 in serum were detected immediately as early as possible. Radiographic severity was detected by Alberta Stroke Program Early CT Score (ASPECTS). Disease severity was evaluated using modified Rankin Scale (mRS). High-sensitivity C-reactive protein (hs-CRP) and matrix metalloproteinase-9 (MMP-9) expression levels were also measured. A correlation analysis was conducted to determine the relationship between the expression levels of SLC7A11 and GPX4 with the clinical severity of the disease and the levels of hs-CRP and MMP-9. Furthermore, receiver operating characteristic (ROC) curve analysis was utilized to assess the potential of SLC7A11 and GPX4 as diagnostic markers.ResultsCompared to the HC group, the serum expression levels of SLC7A11 and GPX4 were significantly lower in the AIS group. Serum SLC7A11 levels were positively associated with serum GPX4 levels. The AIS group included 50 patients with mild neurological impairment, 52 with moderate neurological impairment, and 46 with severe neurological impairment. AIS patients with mild neurological impairment had drastically higher serum SLC7A11 and GPX4 levels compared with those with moderate neurological impairment. AIS patients with moderate neurological impairment showed significantly higher serum SLC7A11 and GPX4 concentrations compared with those with severe neurological impairment. ROC curve analysis demonstrated that both serum SLC7A11 and GPX4 may both act as potential indicators for evaluating of AIS disease severity. In addition, both serum SLC7A11 and GPX4 levels were positively correlated with ASPECTS. Both serum SLC7A11 and GPX4 levels were negatively associated with hs-CRP as well as MMP-9 levels. Serum SLC7A11 and GPX4 levels were significantly increased following comprehensive therapy.ConclusionsDecreased SLC7A11 and GPX4 levels may reflect disease severity of AIS.

The interplay between cancer-associated fibroblasts (CAFs) and extracellular matrix (ECM) mediates progress, metastasis, and therapy resistance. However, strategy of targeting ECM remodeling to enhance chemosensitivity in ovarian cancer remains elusive. Here, a 22-gene matrisome signature predicts chemotherapy response and survival in ovarian cancer. The dense, collagen-rich ECM secreted by CAFs harbors more M2 tumor-associated macrophages (TAMs) than the looser ECM based on single cell RNA-seq (scRNA-seq) of ovarian cancer, suggesting the promising approach of targeting collagen to remodel ECM. An integrated analysis identifies collagen type I alpha 1 chain (COL1A1) as a major component of the ECM that contributes to chemoresistance and poor prognosis, highlighting its potential as a therapeutic target. Halofuginone (HF), a clinically active derivative of febrifugine, is identified as a COL1A1-targeting natural compound by screening the Encyclopedia of Traditional Chinese Medicine (ETCM). Mechanistically, HF inhibits COL1A1 production via the mTOR-eIF2α-ATF4 axis in CAFs. Notably, HF disrupts collagen deposition and promotes CD8+ T cell infiltration, partially via M2-M1 macrophage polarization to enhance chemosensitivity. Overall, the findings suggest that HF combined with chemotherapy is a promising and effective treatment for ovarian cancer.

Targeted therapies and immunotherapies have revolutionized the treatment of metastatic melanoma and have set a successful example for the treatment of other cancers. A similar breakthrough was achieved with the advent of PARP inhibitors (PARPi) in breast and ovarian cancer. Recent evidence highlights the critical role of PARP1 in melanoma initiation and progression. High PARP1 expression correlates with aggressive melanoma characteristics and poor patient outcomes. Preclinical and clinical data suggest that PARPi, alone or in combination, can effectively reduce melanoma cell viability and inhibit tumor growth. However, integrating PARPi with current treatment approaches and identifying patients who could benefit the most from such combinations remain underexplored areas of investigation. This review highlights the need for further basic and clinical research on PARP1 in melanoma, to better understand its role and to tackle major challenges in the field, such as resistance to targeted therapies and immune checkpoint inhibitors.

Ovarian cancer, a gynecologic malignancy with high mortality rates, faces persistent therapeutic challenges due to acquired resistance and frequent recurrence with conventional therapies. While poly (ADP-ribose) polymerase (PARP) inhibitors have primarily transformed clinical outcomes through the synthetic lethality mechanism, their long-term efficacy remains constrained by therapeutic resistance. Ferroptosis, a novel programmed cell death modality characterized by iron-dependent lipid peroxidation, has emerged as a promising therapeutic frontier in oncology. This review is the first to summarize the mechanisms of action and resistance associated with both ferroptosis and PARP inhibitors in ovarian cancer.

Understanding the core principles of ovarian cancer has been significantly improved through the exploration of Ferroptosis, a type of cell death triggered by iron that leads to an increase in lipid peroxides. Current research has shed light on the critical functions of non-coding RNAs, such as circRNAs, lncRNAs, and miRNAs, in regulating ferroptosis in ovarian cancer. The aim of this paper is to comprehensively analyze how ncRNAs influence the development of ferroptosis in ovarian cancer cells. In-depth exploration is undertaken to understand the intricate ways in which ncRNAs regulate essential elements of ferroptosis, including iron management and lipid peroxidation levels. We also investigate their significant involvement in the progression of this type of cellular demise. It should be emphasized that ncRNAs can impact the synthesis of crucial proteins, such as GPX4, a key contributor to the cellular defense against oxidation, and ACSL4, involved in lipid formation. In addition, we examine the correlation between ncRNAs and well-known pathways associated with oxidative stress and cell death. The consequences of these discoveries are noteworthy, since focusing on particular ncRNAs could potentially render ovarian cancer cells more vulnerable to ferroptosis, effectively combating drug resistance problems. This discussion highlights the growing significance of ncRNAs in governing ferroptosis and their potential as useful biomarkers and treatment targets for ovarian cancer. We intend to promote additional research into the involvement of ncRNAs in controlling ferroptosis, based on current findings, with the ultimate goal of informing targeted therapeutic strategies and improving long-term treatment outcomes for individuals suffering from OC.

Recently, several studies have reported that nucleus pulposus (NP) cell ferroptosis plays a key role in IDD. However, the characteristics and molecular mechanisms of cell subsets involved remain unclear. We aimed to define the key factors driving ferroptosis, and the characteristics of ferroptotic NP cells subsets during IDD.

The accumulation of iron ions in NP tissues of rats caudal intervertebral discs (IVDs) was determined by Prussian blue staining. Fluorescent probe Undecanoyl Boron Dipyrromethene (C11-BODIPY) and lipid peroxidation product 4-Hydroxynonenal (4-HNE) staining were performed to assess lipid peroxidation level of NP cells. The differentially expressed genes in NP tissues with aging were overlapped with FerrDB database to screen ferroptosis driving genes associated with aging-related IDD. In addition, single cell sequencing (ScRNA-seq) was used to map the NP cells, and further identify ferroptotic NP cell subsets, as well as their crucial drivers. Finally, cluster analysis was performed to identify the marker genes of ferroptotic NP cells.

Histological staining showed that, compared with 10 months old (10M-old) group, the accumulation of iron ions increased in NP tissues of 20 months old (20M-old) rats, and the level of lipid peroxidation was also enhanced. 15 ferroptosis driving factors related to IDD were selected by cross-enrichment. ScRNA-seq identified 14 subsets in NP tissue cells, among which the number and ratio of 5 subsets was reduced, and the intracellular ferroptosis related signaling pathways were significantly enriched, accompanied by enhanced cell lipid peroxidation. Notably, ranking the up-regulation fold of ferroptosis related genes, we found Atf3 was always present within TOP2 of these five cell subsets, suggests it is the key driving factor in NP cell ferroptosis. Finally, cluster cross-enrichment and fluorescence colocalization analysis revealed that Rps6 +/Cxcl1- was a common molecular feature among the 5 ferroptotic NP cell subsets.

This study reveals that ATF3 is a key driver of NP cell ferroptosis during IDD, and Rps6 +/Cxcl1- is a common molecular feature of ferroptotic NP cell subsets. These findings provide evidence and theoretical support for subsequent targeted intervention of NP cell ferroptosis, as well as provide directions for preventing and delaying IDD.

Programmed cell death is a mechanism that is crucial for numerous physiological and pathological processes. Whereas p53-mediated apoptosis is a major cell death pathway in cancer, accumulating evidence indicates that p53 also has crucial roles in controlling different non-apoptotic cell death (NACD) pathways, including ferroptosis, necroptosis, pyroptosis, autophagy-dependent cell death, entotic cell death, parthanatos and paraptosis, and may regulate PANoptosis, cuproptosis and disulfidptosis. Notably, the function of p53 in these NACDs substantially contributes to its biological effects, particularly in cancer development and other pathological processes. In this Review, we discuss recent advances in understanding the roles and underlying mechanisms of p53-mediated NACDs, focusing on ferroptosis, necroptosis and pyroptosis. We discuss the complex and distinct physiological settings in which NACDs are regulated by p53, and potential targeting of p53-regulated NACDs for the treatment of cancer and other human diseases. Finally, we highlight several important questions concerning p53-regulated NACDs that warrant further investigation.

Ovarian cancer (OV) is the leading cause of death among gynecological malignancies. This study aimed to investigate the influence of Icariside II on OV in vitro and in vivo and to elucidate whether Icariside II induces ferroptosis in OV cells by regulating SLC7A11 expression.

SKOV3 cells and OV nude mice were treated with Icariside II, a control-plasmid or an SLC7A11-plasmid. EdU assay, flow cytometry, wound-healing assay, and Transwell assays were used to assess cell proliferation, apoptosis, migration, and invasion respectively. Total iron, Fe2+ levels, and intracellular lipid reactive oxygen species (ROS) stimulation were evaluated in both cells and tissues. Levels of cysteine (Cys), glutathione (GSH), and glutathione peroxidase 4 (GPX4) were also analyzed. Ferroptosis markers, including Ptgs2, Chac1, SLC7A11, and apoptosis-associated genes (Bax and Bcl-2), were detected using qRT-PCR, western blotting, and immunohistochemistry (IHC). SLC7A11 expression in OV was explored using data from The Cancer Genome Atlas (TCGA), and validated with IHC staining.

Icariside II-induced ferroptosis in OV cells was confirmed by elevated Fe2+ and total iron levels, enhanced lipid ROS levels, higher Ptgs2 and Chac1 mRNA levels, and reduced levels of SLC7A11, Cys, GSH, and GPX4 in both in vitro and in vivo models. These effects were partially reversed by the SLC7A11-plasmid. Moreover, Icariside II suppressed SKOV3 cell proliferation, inhibited cells migration and invasion, and promoted apoptosis by downregulating SLC7A11 expression. Furthermore, we found that SLC7A11 expression was upregulated in OV tissues compared to adjacent non-tumor tissues.

Icariside II induces ferroptosis in OV by downregulating SLC7A11 expression in vitro and in vivo. Our study identified Icariside II as a promising therapeutic agent for the treatment of OV.

Ferroptosis, a regulated form of cell death driven by iron-dependent lipid peroxidation, has emerged as a critical factor in female reproductive health and has been implicated in disorders such as polycystic ovary syndrome, premature ovarian insufficiency, endometriosis, and ovarian cancer. This review explores the intricate molecular mechanisms underlying ferroptosis, emphasizing its reliance on iron metabolism and oxidative stress, which disrupt key processes in reproductive tissues, including granulosa cell function, folliculogenesis, and embryo implantation. Increasing evidence linking ferroptosis to these conditions offers new therapeutic opportunities, with iron chelators, lipid peroxidation inhibitors, and antioxidants showing the potential to alleviate reproductive dysfunction by modulating ferroptotic pathways. In ovarian cancer, ferroptosis inducers combined with conventional cancer therapies, such as chemotherapy, provide promising strategies to overcome drug resistance. This review synthesizes current knowledge on ferroptosis and highlights its importance as a therapeutic target in reproductive health, emphasizing the need for further research to refine and expand treatment options, evaluate their applicability in clinical settings, and explore their role in fertility preservation. By advancing our understanding of ferroptosis regulation, these therapeutic approaches could lead to novel treatments for reproductive disorders and cancers, offering new hope for improving outcomes in women's health and cancer therapy.

Cancer is the main leading cause of death worldwide and poses a great threat to human life and health. Although pharmacological treatment with chemotherapy and immunotherapy is the main therapeutic strategy for cancer patients, there are still many shortcomings during the treatment such as incomplete killing of cancer cells and development of drug resistance. Emerging evidence indicates the promise of inducing ferroptosis for cancer treatment, particularly for eliminating aggressive malignancies that are resistant to conventional therapies. This review covers recent advances in important regulatory targets in the ferroptosis metabolic pathway and ferroptosis inducers (focusing mainly on the last 3 years) to delineate their design, mechanisms of action, and anticancer applications. To date, many compounds, including inhibitors, degraders, and active molecules from traditional Chinese medicine, have been demonstrated to have ferroptosis-inducing activity by targeting the different biomolecules in the ferroptosis pathway. However, strictly defined ferroptosis inducers have not yet been approved for clinical use; therefore, the discovery of new highly active, less toxic, and selective compounds remains the goal of further research in the coming years.

Infection with carbapenem-resistant hypervirulent Klebsiella pneumoniae (CR-hvKP) is life-threatening because of its pronounced virulence and antibiotic resistance. Recent studies revealed that iron and ROS enhance the ability of macrophages to eliminate intracellular pathogenic bacteria. However, whether and how iron-related oxygen stress responses in macrophages elicit a protective role against CR-hvKP infection remains largely unknown. In a mouse model of CR-hvKP pulmonary infection, the production of the Solute Carrier Family 7 member 11 (SLC7A11) was increased. Treatment with the ferroptosis agonist Erastin or Sorafenib decreased the SLC7A11 expression and the bacterial load in infected lung tissues, alleviating CR-hvKP-induced acute lung injury, increasing the content of TLR4, ROS and LPO. In vitro experiments showed that CR-hvKP infection resulted in a remarkable time-dependent changes in the expression of SLC7A11, GSH, ferrous iron, ROS and LPO in MH-S cells. Mechanically, blocking the expression of SLC7A11 in CR-hvKP-infected MH-S cells increased iron and ROS, improving the ability of macrophages to clear CR-hvKP in an LPO-dependent manner. Taken together, our study reveals that improving iron-related oxygen stress via blocking the SLC7A11/GSH pathway promoting the macrophages to phagocytose and eliminate CR-hvKP, which provides a new promising strategy against CR-hvKP infection.

Parkinson's disease (PD) is a common neurodegenerative disorder characterized by the degeneration of dopaminergic neurons and the aggregation of α-synuclein. Neuroinflammation is triggered by the activation of microglia and astrocytes, which release pro-inflammatory factors that exacerbate neuronal damage. This inflammatory state also disrupts iron homeostasis, leading to the occurrence of ferroptosis. Ferroptosis is characterized by lipid peroxidation of cell membranes and iron overload. Abnormal accumulation of iron in the brain increases oxidative stress and lipid peroxidation, further aggravating neuroinflammation and damage to dopaminergic neurons. Natural products have garnered attention for their antioxidant, anti-inflammatory, and neuroprotective properties, with many plant extracts showing promising therapeutic potential in PD research. This study further investigates the potential therapeutic roles of various natural products in regulating neuroinflammation and ferroptosis. The results suggest that natural products have significant therapeutic potential in modulating the interaction between neuroinflammation and ferroptosis, making them potential treatments for PD. Future research should further validate the safety and efficacy of these natural compounds in clinical applications to develop novel therapeutic strategies for PD.

Mutations in the tumor suppressor genes BRCA1 and BRCA2 are associated with the triple-negative breast cancer phenotype, particularly aggressive and hard-to-treat tumors lacking estrogen, progesterone, and human epidermal growth factor receptor 2. This research aimed to understand the metabolic and genetic links behind BRCA1 and BRCA2 mutations and investigate their relationship with effective therapies. Using the Cytoscape software, two networks were generated through a bibliographic analysis of articles retrieved from the PubMed-NCBI database. We identified 98 genes deregulated by BRCA mutations, and 24 were modulated by therapies. In particular, BIRC5, SIRT1, MYC, EZH2, and CSN2 are influenced by BRCA1, while BCL2, BAX, and BRIP1 are influenced by BRCA2 mutation. Moreover, the study evaluated the efficacy of several promising therapies, targeting only BRCA1/BRCA2-mutated cells. In this context, CDDO-Imidazolide was shown to increase ROS levels and induce DNA damage. Similarly, resveratrol decreased the expression of the anti-apoptotic gene BIRC5 while it increased SIRT1 both in vitro and in vivo. Other specific drugs were found to induce apoptosis selectively in BRCA-mutated cells or block cell growth when the mutation occurs, i.e., 3-deazaneplanocin A, genistein or daidzein, and PARP inhibitors. Finally, over-representation analysis on the genes highlights ferroptosis and proteoglycan pathways as potential drug targets for more effective treatments.

Ovarian cancer (OC) is prone to peritoneum or omentum dissemination, thus giving rise to the formidable challenge of unresectable surgery and a dismal survival rate. Although niraparib holds a pivotal role in the maintenance treatment of OC, its effect on suppressing metastases during primary intervention remains enigmatic. Recently, we initiated a prospective clinical study (NCT04507841) in order to evaluate the therapeutic efficacy of neoadjuvant niraparib monotherapy for advanced OC with homologous recombination deficiency. An analysis of patient tumor burden before and after the niraparib challenge showed a remarkable vulnerability of OC intraperitoneal metastases to niraparib exposure. This killing capacity of niraparib was closely associated with the accumulation of fatty acids within the abdomen, which was confirmed by the increased susceptibility of tumor cells to niraparib treatment in the presence of fatty acids. In the context of abundant fatty acids, niraparib elevated intracellular levels of fatty acids and lipid peroxidation, leading to subsequent tumor cell ferroptosis in a p53 and BRCA-independent manner. Notably, under niraparib exposure, a critical fatty acid transporter CD36 was dramatically upregulated in tumors, facilitating excessive uptake of fatty acids. Pharmacological inhibition of either ferroptosis or CD36 impaired the anti-tumor activity of niraparib both in vitro and in murine intraperitoneal ID8 tumor models. Our findings demonstrate ferroptosis as a novel mechanism underlying the regression of OC metastases induced by niraparib, thereby offering tantalizing prospects for the frontline application of this agent in the management of OC.

Parkinson's disease (PD), a common neurodegenerative disorder, is characterized by progressive loss of dopaminergic neurons, and accumulation of α-synuclein in the substantial nigra. Emerging evidence identifies ferroptosis as a regulated iron-dependent cell death mechanism marked by excessive lipid peroxidation (LPO) as a key contributor to PD pathogenesis. Ferroptosis is intertwined with critical disease processes such as aggregation of α-synuclein protein, oxidative stress generation, mitochondrial alteration, iron homeostasis dysregulation, and neuroinflammation. This mechanism disrupts cellular homeostasis by impairing iron metabolism and antioxidant pathways like the xc-/glutathione/GPX4 axis and the CoQ10 pathway. This review consolidates current advancements in understanding ferroptosis in these mechanisms, increasing interest in contribution to PD pathology. In addition, it explores the latest developments in ferroptosis-targeting pharmacological agents, including their application in the preclinical and clinical study, and highlights their potential to revolutionize PD management. Unraveling the interplay between ferroptosis and PD offers a transformative perspective, paving the way for innovative therapies to combat this debilitating disease condition.

Ferroptosis plays a vital role in cancer development and treatment. The relationship between ferroptosis-related genes and breast cancer prognosis, as well as immunotherapy outcomes, remains unknown.

To evaluate the prognostic value of ferroptosis-related genes in breast cancer.

We conducted differential expressions and prognostic analysis for ferroptosis-related genes on public databases and breast cancer patients in our center and analyzed their predictive value for immunotherapy of breast cancer patients.

We identified prognostic ferroptosis-related genes, constructed a nomogram, and validated key genes using patient data from our center. We also investigated ferroptosis-related genes significantly associated with immune infiltration and identified FTH1 as a promising biomarker for triple-negative breast cancer immunotherapy.

Ferroptosis-related genes had potential prognostic value and predictive value for breast cancer immunotherapy.

The battle against cancer has evolved over centuries, from the early stages of surgical resection to contemporary treatments including chemotherapy, radiation, targeted therapies, and immunotherapies. Despite significant advances in cancer treatment over recent decades, these therapies remain limited by various challenges. Immune checkpoint inhibitors (ICIs), a cornerstone of tumor immunotherapy, have emerged as one of the most promising advancements in cancer treatment. Although ICIs, such as CTLA-4 and PD-1/PD-L1 inhibitors, have demonstrated clinical efficacy, their therapeutic impact remains suboptimal due to patient-specific variability and tumor immune resistance. Cell death is a fundamental process for maintaining tissue homeostasis and function. Recent research highlights that the combination of induced regulatory cell death (RCD) and ICIs can substantially enhance anti-tumor responses across multiple cancer types. In cells exhibiting high levels of recombinant solute carrier family 7 member 11 (SLC7A11) protein, glucose deprivation triggers a programmed cell death (PCD) pathway characterized by disulfide bond formation and REDOX (reduction-oxidation) reactions, termed "disulfidptosis." Studies suggest that disulfidptosis plays a critical role in the therapeutic efficacy of SLC7A11high cancers. Therefore, to investigate the potential synergy between disulfidptosis and ICIs, this study will explore the mechanisms of both processes in tumor progression, with the goal of enhancing the anti-tumor immune response of ICIs by targeting the intracellular disulfidptosis pathway.

Ovarian cancer (OC) is one of the most fatal gynecological neoplasms. Meta-analyses have shown that the relationship between body mass index (BMI) and ovarian cancer incidence was detected in some types of ovarian cancer. Chronic inflammation and excessive accumulation of free fatty acids are key adipose tissue-derived factors initiating cancer development. Cancer cells transform adipose-derived stem cells into cancer-associated adipocytes, which produce adipokines and interleukins. It was revealed that adipokines exert a pleiotropic role in ovarian cancer pathogenesis. Chemerin presents both pro-cancer and anti-cancer action in ovarian cancer development. Chemerin induces angiogenesis and increases programmed death ligand-1 (PD-L1) expression, leading to enhanced proliferation and migration of OC cells. Apelin impacts cancer cell migration and acts as a mitogenic factor. Moreover, apelin exerts influence on lipid uptake into cancer cells and accelerates fatty acid oxidation, which provides energy for cancer cells. Visfatin induces matrix metallopeptidase 2 (MMP2) expression involved in extracellular matrix degradation and suppresses claudin 3 and 4 expression. Visfatin also induces a shift to anaerobic glucose metabolism and influences poly-ADP ribose polymerase (PARP). Resistin induces MMP2 and vascular endothelial growth factor (VEGF) expression and contributes to cisplatin-resistance development. A substantial body of evidence indicates that antagonists of adipokines mitigate OC progression, and adipokines are gaining gradual recognition as a potential therapeutic aim in ovarian cancer targeted therapy.

Messenger RNA (mRNA) translational control plays a pivotal role in regulating cellular proteostasis under physiological and pathological conditions. Dysregulated mRNA translation is pervasive in cancer, in which protein synthesis is elevated to support accelerated cell growth and proliferation. Consequently, targeting the mRNA translation machinery has emerged as a therapeutic strategy to treat cancer. In this Perspective, we summarize the current knowledge of translation dysregulation in cancer, with emphasis on the eukaryotic translation initiation factor 4F complex. We outline recent endeavors to apply this knowledge to develop novel treatment strategies to combat cancer.

Ovarian cancer remains a significant challenge due to the lack of effective treatment and the resistance to conventional therapies. Ferroptosis, a form of regulated cell death characterized by iron-depend and lipid peroxidation, has emerged as a potential therapeutic target in cancer. Ovarian cancer has been reported to exert an "iron addiction" phenotype which makes it is susceptible to ferroptosis inducers. However, we found here that high-adhesion ovarian cancer cells were resistant to ferroptosis. Mechanistically, by PCR array, we identified junctional adhesion molecule 3 (JAM3) as a key mediator of ferroptosis resistance in high-adhesion ovarian cancer cells. Knockdowning and blocking JAM3 sensitized cancer cells to ferroptosis inducers RSL3 and erastin, while JAM3 overexpression conferred resistance to these agents. In addition, JAM3 also promoted ovarian cancer cells resistance to chemotherapeutic agent cisplatin in vitro and in vivo by inhibiting ferroptosis. Furthermore, we demonstrated that JAM3 promoted ferroptosis resistance through NRF2-induced upregulation of FSP1, a critical suppressor of lipid peroxidation. Inhibition of the NRF2/FSP1 pathway eliminated high-adhesion, JAM3 overexpressed ovarian cancer cells resistance to ferroptosis, and decreased cancer cells resistance to cisplatin. Moreover, JAM3 high expression was associated with poor prognosis in patients with ovarian cancer. Altogether, this study provided novel insights into the molecular mechanisms underlying ferroptosis resistance and identify JAM3 as a potential therapeutic target for combating drug resistance in ovarian cancer.

Rheumatoid arthritis (RA) is an autoimmune disease of unknown etiology. This study aims to explore the potential mechanisms by which solute carrier family 7 member 11 (SLC7A11) influences RA development.

Collagen-induced arthritis (CIA) mice were constructed to observe disease onset and pathological scores. Pathological changes were examined using Hematoxylin-eosin and Safranin O-Fast Green staining. Levels of lactate dehydrogenase (LDH), inflammatory cytokines (tumor necrosis factor [TNF]-α, interleukin [IL]-18 and IL-1β), and oxidative stress (reactive oxygen species, malondialdehyde, and glutathione) were measured using ELISA. Western blotting was performed to detect the expression of pyroptosis- and pathway-related proteins. Fibroblast-like synoviocytes of RA (RA-FLS) were treated with TNF-α. Cell migration, invasion, and Caspase-1 levels were assessed through scratch assays, Transwell assays, and flow cytometry, respectively. The correlation between SLC7A11 and immune cell infiltration in RA was analyzed using bioinformatics. Additionally, downstream pathways of SLC7A11 in RA were screened, and the impacts of SLC7A11 on these pathways were validated in vitro.

CIA mice were successfully established, revealing significant downregulation of SLC7A11 in RA. Staining results indicated that overexpression of SLC7A11 significantly mitigated joint damage in CIA mice. In vitro experiments demonstrated that overexpression of SLC7A11 inhibited migration, invasion, and Caspase-1 expression levels in TNF-α-induced RA-FLSs. Furthermore, SLC7A11 suppressed inflammation, LDH release, and oxidative stress, while inhibiting pyroptosis. SLC7A11 expression was significantly different in multiple immune cells. The IL-17 pathway was identified as a downstream pathway of SLC7A11, and SLC7A11 inhibited the expression of IL-17 pathway proteins. Additionally, rhIL-17A, an activator of the IL-17 pathway, attenuated the inhibitory effects of SLC7A11 on inflammation, oxidative stress, and pyroptosis.

SLC7A11 suppresses pyroptosis to alleviate RA development by inhibiting the IL-17 pathway.

Lysophosphatidylcholine acyltransferase 3 (LPCAT3) promotes ferroptosis through the incorporating polyunsaturated fatty acids into membrane phospholipids, however, its role in serous ovarian cancer remains unclear. Here explored cancer proliferation and metastasis after modulating LPCAP3.

LPCAT3 protein in ovarian cancer tissues was detected using bioinformatic and immunohistoche mical assays. Cell behaviors were observed after up- or down-regulating LPCAT3. Lipid metabolites were determined, and then the pathway enrichment analysis was performed.

The expression level of LPCAT3 in serous ovarian cancer tissues was lower than that in other types of ovarian cancer, and high expression was associated with a longer survival time. Overexpressing LPCAT3 reduced cell proliferation, migration and invasion via enhancing ferroptosis and decreasing the survival signaling; these behaviors were enhanced in LPCAT3-downknocked cells, where a higher abundance of arachidonic acid was observed followed by up-regulation of the downstream survival signaling. In vivo, up-regulation of LPCAT3 decreased tumor growth, but down-regulation enhanced tumor growth and metastasis.

LPCAT3 modulated metabolism of arachidonic acid, thereby regulating ferroptosis and the survival signaling to determine cancer growth and metastasis.

Resistance to olaparib inevitably develops in ovarian cancer (OC) patients, highlighting the necessity for effective strategies to improve its efficacy. Here, we established a novel olaparib-resistant patient-derived xenograft model of high-grade serous OC with BRCA1/2 mutations and examined the molecular characteristics of acquired resistance and resensitization to olaparib in treatment-naïve tumors in vivo. Olaparib-resistant xenografts were treated with olaparib, ATR inhibitor (ATRi, ceralasertib), CHK1 inhibitor (CHK1i, MK-8776) or their combinations. Proliferation, apoptosis, ATR/CHK1 activity, PARP signaling, DNA damage response (DDR), epithelial-to-mesenchymal transition (EMT), and MDR1 expression, were examined via RT-qPCR, western blot, and immunohistochemistry. Resistant tumors exhibited defects in PARP and ATR/CHK1 signaling, accompanied by altered expression of proteins involved in DDR and EMT. Olaparib rechallenge combined with ATR/CHK1 inhibitors showed promising synergistic effects on tumor growth inhibition. Mechanistically, combined treatments suppressed tumor proliferation without increasing apoptosis or necrosis, while inducing tumor cell vacuolization indicative of cell death. ATRi combined with olaparib induced or augmented downregulation of ATR, CHK1, PARP1, PARG, BRCA1, γH2AX, and PARylated protein expression, while reversing olaparib-induced upregulation of vimentin, BRCA2, and 53BP1. Our collective findings indicate that ATR/CHK1 pathway inhibition restores the olaparib efficacy in resistant BRCA1/2MUT high-grade serous OC, highlighting promising approach for olaparib rechallenge of non-responsive patients. Uncovered mechanisms might improve our understanding of acquisition and overcoming resistance to olaparib in ovarian cancer.

Ferroptosis is a form of programmed cell death that is distinct from apoptosis. The mechanism involves redox‑active metallic iron and is characterized by an abnormal increase in iron‑dependent lipid reactive oxygen species, which results in high levels of membrane lipid peroxides. The relationship between ferroptosis and gynaecological tumours is complex. Ferroptosis can regulate tumour proliferation, metastasis and chemotherapy resistance, and targeting ferroptosis is a promising antitumour approach. Ferroptosis interacts with mechanisms related to tumorigenesis and development, such as macrophage polarization, the neutrophil trap network, mitochondrial autophagy and cuproptosis. The present review examines recent information on the interaction between the molecular mechanism of ferroptosis and other tumour‑related mechanisms, as well as the involvement of ferroptosis in gynaecological tumours, to identify implications for gynaecological cancer therapy.

Epigenetic abnormalities play a critical role in colon carcinogenesis, making them a promising target for therapeutic interventions. In this study, we demonstrated that curcumin reduces colon cancer cell survival and that a decrease in lysine methylation was involved in such an effect. This correlated with the downregulation of methyltransferases EZH2, MLL1, and G9a, in both wild-type p53 (wtp53) HCT116 cells and mutant p53 (mutp53) SW480 cells, as well as SET7/9 specifically in wtp53 HCT116 cells. The effects induced by curcumin were more pronounced in wtp53 cells, where it induced a stronger apoptosis and ferroptosis. Interestingly, curcumin also reduced mutp53 expression, suggesting that it could enhance the efficacy of other therapies, particularly in overcoming drug resistance mechanisms associated with mutp53. For instance, in this study, we show that curcumin sensitized SW480 cells to SET7/9 inhibition by sinefungin, further supporting its potential as a combinatorial therapeutic agent. However, although to a lesser extent, curcumin also impaired cell survival in HCT 116 p53 null cells, suggesting that other molecular pathways or factors, beyond p53, may be involved in curcumin-induced cytotoxicity.

Despite advances in various chemotherapy regimens, current therapeutic options are limited for ovarian cancer patients. Oxidative stress-induced growth inhibitor 1 (OSGIN1), which is a tumor suppressor gene known to regulate the cellular stress response and apoptosis, is associated with ovarian cancer development. However, the underlying mechanisms involved in ferroptosis regulation have not been elucidated. Thus, this study aimed to investigate the effect and underlying regulatory mechanism of the OSGIN1 gene on ovarian cancer cells. Our results demonstrated that loss of the OSGIN1 gene promoted ovarian cancer growth and conferred resistance to drug-induced ferroptosis. Mechanistically, the loss of OSGIN1 activates AMPK signaling through ATM, leading to the upregulation of SLC2A3, which protects cells from ferroptosis and renders them insensitive to ferroptosis inducers. Notably, an SLC2A3-neutralizing antibody enhances the ferroptosis-inducing and anticancer effects of sorafenib on ovarian cancer patient-derived xenograft tumors. Overall, anti-SLC2A3 therapy is a promising method to improve ovarian cancer treatment by targeting ferroptosis.

Ferroptosis is an iron-dependent form of programmed cell death induced by lipid peroxidation. This process is regulated by signaling pathways associated with redox balance, iron metabolism, and lipid metabolism. Cancer cells' increased iron demand makes them especially susceptible to ferroptosis, significantly influencing cancer development, therapeutic response, and metastasis. Recent findings indicate that cancer cells can evade ferroptosis by downregulating key signaling pathways related to this process, contributing to drug resistance. This underscores the possibility of modulating ferroptosis as an approach to counteract drug resistance and enhance therapeutic efficacy. This review outlines the signaling pathways involved in ferroptosis and their interactions with cancer-related signaling pathways. We also highlight the current understanding of ferroptosis in cancer drug resistance, offering insights into how targeting ferroptosis can provide novel therapeutic approaches for drug-resistant cancers. Finally, we explore the potential of ferroptosis-inducing compounds and examine the challenges and opportunities for drug development in this evolving field.

Although cell-cycle arrest, senescence, and apoptosis are well accepted as the classic barriers in tumorigenesis, recent studies indicate that metabolic regulation is equally important as a major checkpoint in cancer development. It is well accepted that ferroptosis, an iron-dependent programmed cell death, acts as a new type of tumor suppression mechanism tightly linked with numerous metabolic pathways. SLC7A11 is a transmembrane cystine/glutamate transporter protein that plays a vital role in controlling ferroptosis in vivo. The levels of SLC7A11 are dynamically regulated by various types of stresses, such as oxidative stress, nutrient deprivation, endoplasmic reticulum stress, radiation, oncogenic stress, DNA damage, and immune stress. SLC7A11 can be transcriptionally regulated by both activators such as ATF4, NRF2, and ETS1, and repressors including BACH1, p53, ATF3, and STAT1 during stress responses. Moreover, SLC7A11 activity and its protein stability and cellular localization are also modulated upon stress. Patients' data show that SLC7A11 is overexpressed in various types of human cancers, and higher levels of SLC7A11 predict poorer overall survival. Growing evidence also suggests that targeting SLC7A11 is a promising approach in cancer therapy by effectively inhibiting tumor proliferation, invasion, and metastasis, as well as counteracting cancer stem cells and overcoming chemoresistance. This review highlights the regulation of SLC7A11 as an unconventional checkpoint in tumorigenesis through modulating ferroptotic responses under various types of stress.

Tumor suppressor p53-mediated cell cycle arrest and DNA damage repair may exert cytoprotective effects against cancer therapies, including WEE1 inhibition. Considering that p53 activation can also lead to multiple types of cell death, the role of this tumor suppressor in WEE1 inhibitor-based therapies remains disputed. In this study, we reported that nucleolar stress-mediated p53 activation enhanced the WEE1 inhibitor AZD1775-induced ferroptosis to suppress lung cancer growth. Our findings showed that AZD1775 promoted ferroptosis by blocking cystine uptake, an action similar to that of Erastin. Meanwhile, inhibition of WEE1 by the WEE1 inhibitors or siRNAs induced compensatory upregulation of SLC7A11, which conferred resistance to ferroptosis. Mechanistically, AZD1775 prevented the enrichment of H3K9me3, a histone marker of transcriptional repression, on the SLC7A11 promoter by repressing the expression of the histone methyltransferase SETDB1, thereby enhancing NRF2-mediated SLC7A11 transcription. This finding was also validated using the H3K9me3 inhibitor BRD4770. Remarkably, we found that the nucleolar stress-inducing agent Actinomycin D (Act. D) inhibited SLC7A11 expression by activating p53, thus augmenting AZD1775-induced ferroptosis. Moreover, the combination of AZD1775 and Act. D synergistically suppressed wild-type p53-harboring lung cancer cell growth both in vitro and in vivo. Altogether, our study demonstrates that AZD1775 promotes ferroptosis by targeting cystine uptake but also mediates the adaptive activation of SLC7A11 through the WEE1-SETDB1 cascade and NRF2-induced transcription, and inhibition of SLC7A11 by Act. D boosts the anti-tumor efficacy of AZD1775 by enhancing ferroptosis in cancers with wild-type p53.

Resistance to cytarabine is a major obstacle to the successful treatment of acute myeloid leukemia (AML). The present study aimed to explore the mechanism by which sirtuin 1 (SIRT1) reverses the cytarabine resistance of leukemia cells. Cell viability was investigated using the EdU proliferation assay. The expression levels of molecules were determined by reverse transcription‑quantitative PCR, western blotting, and immunofluorescence staining. Flow cytometry was used to detect reactive oxygen species and apoptosis levels, The levels of superoxide dismutase, glutathione and malondialdehyde were examined by ELISA. Mitochondrial damage was investigated by transmission electron microscopy. Furthermore, tumor growth was evaluated in a xenograft model. The results revealed that SIRT1 expression was significantly upregulated in drug‑resistant leukemia cells. By contrast, knockdown of SIRT1 reversed cytarabine resistance in HL60 cells by promoting ferroptosis. Mechanistically, SIRT1 could regulate the translocation of HMGB1 from the nucleus to the cytoplasm in cytarabine‑resistant HL60 (HL60/C) cells. Furthermore, knockdown of HMGB1 inhibited the expression of ACSL4. In addition, knockdown of SIRT1 expression could inhibit the growth of HL60/C cells in vivo and reverse cytarabine resistance. In conclusion, the present results demonstrated that SIRT1 inhibition could be a promising strategy to overcome cytarabine resistance in AML.

Ferroptosis, iron-dependent regulated cell death, is induced by the polyunsaturated fatty acid peroxidation of membrane phospholipids and is controlled by glutathione peroxidase 4. In recent years, convincing evidence has emerged, demonstrating a close relationship between chemo-, radio-, immuno-, and targeted therapy resistance and ferroptosis resistance. In this review, we discuss the basic principles of ferroptosis in cancer. Considerable attention is paid to the formation of an immunosuppressive tumor microenvironment. The main focus is centered on the involvement of the excessive, chronic production of pro-inflammatory cytokines in ferroptosis resistance development in tumors.

Ferroptosis is a form of cell death that occurs when there is an excess of reactive oxygen species (ROS), lipid peroxidation, and iron accumulation. The precise regulation of metabolic pathways, including iron, lipid, and amino acid metabolism, is crucial for cell survival. This type of cell death, which is associated with oxidative stress, is controlled by a complex network of signaling molecules and pathways. It is also implicated in various respiratory diseases such as asthma, chronic obstructive pulmonary disease (COPD), acute lung injury (ALI), lung cancer, pulmonary fibrosis (PF), and the coronavirus disease 2019 (COVID-19). To combat drug resistance, it is important to identify appropriate biological markers and treatment targets, as well as intervene in respiratory disorders to either induce or prevent ferroptosis. The focus is on the role of ferroptosis in the development of respiratory diseases and the potential of targeting ferroptosis for prevention and treatment. The review also explores the interaction between immune cell ferroptosis and inflammatory mediators in respiratory diseases, aiming to provide more effective strategies for managing cellular ferroptosis and respiratory disorders.

In 2020, breast cancer surpassed lung cancer as the most common cancer in the world for the first time. Due to the resistance of some breast cancer cell lines to apoptosis, the therapeutic effect of anti-breast cancer drugs is limited. According to recent report, the susceptibility of breast cancer cells to ferroptosis affects the progress, prognosis and drug resistance of breast cancer. For instance, roblitinib induces ferroptosis of trastuzumab-resistant human epidermal growth factor receptor 2 (HER2)-positive breast cancer cells by diminishing fibroblast growth factor receptor 4 (FGFR4) expression, thereby augmenting the susceptibility of these cells to HER2-targeted therapies. In tamoxifen-resistant breast cancer cells, Fascin exacerbates their resistance by repressing solute carrier family 7 member 11 (SLC7A11) expression, which in turn heightens their responsiveness to tamoxifen. In recent years, Chinese herbs extracts and therapeutic drugs have been demonstrated to elicit ferroptosis in breast cancer cells by modulating a spectrum of regulatory factors pertinent to ferroptosis, including SLC7A11, glutathione peroxidase 4 (GPX4), acyl-CoA synthetase long chain family member 4 (ACSL4), and haem oxygenase 1 (HO-1). Here, we review the roles and mechanisms of Chinese herbal extracts and therapeutic drugs in regulating ferroptosis in breast cancer, providing potential therapeutic options for anti-breast cancer.

Rationale: Ferroptosis and sonodynamic therapy (SDT) are both promising therapeutic modalities, but their clinical application remains challenging due to the hypoxic tumor microenvironment and limited supply of polyunsaturated fatty acids. Developing an agent with oxygen-enhanced SDT and increased ferroptosis sensitivity is crucial for advancing tumor therapy. Methods: In this study, catalase (Cat) and Acyl-CoA synthetase long-chain family member 4 (ACSL4) highly expressed 4T1 cells were constructed via lentivirus transfection. Cat and ACSL4 enriched exosomes (EXO@CA) were then extracted and loaded with the sonosensitizer tetrakis (4-carboxyphenyl) porphyrin (TCPP) through electroporation to create engineered exosomes (EXO@CAT). We evaluated the ability of EXO@CAT to generate oxygen in a hydrogen peroxide environment and investigated its effect on motion profiles and permeability of EXO@CAT. The in vitro antitumor activity was assessed via cytotoxicity, ROS levels, live/dead staining, and apoptosis, with ferroptosis biomarkers confirming ferroptosis activation. We also evaluated the in vivo anticancer efficacy of EXO@CAT by tumor growth analysis and histological and immunohistochemical staining in mouse models bearing breast tumor. Results: EXO@CAT harnesses ultrasound stimulation to facilitate oxygen-enriched SDT, demonstrating significant capacity for singlet oxygen (1O2) generating, which promotes the accumulation of lipid peroxidation (LPO), ultimately leading to the induction of ferroptosis. Concurrently, ACSL4 released from EXO@CAT also increases LPO accumulation by modifying cellular lipid composition, thereby enhancing cellular sensitivity to ferroptosis. Moreover, both in vitro and in vivo experiments demonstrate that the homologous targeting ability of EXO@CAT enables its efficient accumulation in tumor tissues, and the oxygen generation catalyzed by Cat not only alleviates tumor hypoxia but also facilitates the penetration of EXO@CAT into deeper layers of tumor tissue. Conclusions: EXO@CAT combines endogenous proteins, which are prone to inactivation, with an exogenous sonosensitizer, allowing synergistic anticancer treatment of both ferroptosis and SDT with improved efficacy.