Ferroptosis is an iron-dependent form of cell death driven by lipid peroxidation1. Here we identify spermine-a polyamine derived from spermidine2-as an endogenous iron chelator that directly suppresses ferroptosis. Integrating metabolomics, stable isotope tracing and biophysical studies of the interaction between spermine and Fe2+ ions, we demonstrate that aldehyde dehydrogenase 18 family member A1 (ALDH18A1) promotes an alternative glutamine-dependent pathway for de novo spermine synthesis. This process limits iron availability and lipid peroxidation in hepatocellular carcinoma. Genetic or pharmacological inhibition of ALDH18A1-through knockout, short hairpin RNA delivered using adeno-associated virus (AAV), or the small molecule inhibitor YG1702-triggers ferroptosis and impairs both spontaneous and chemically induced hepatocarcinogenesis. Conversely, supplementation of spermine protects against ferroptosis-associated ischaemia-reperfusion injury across multiple tissues, including the liver, intestine and kidneys. These findings uncover a pathophysiologically relevant metabolic circuit in which spermine-mediated iron chelation suppresses ferroptosis.

This study aims to inform clinical decision-making by identifying metabolism-related biomarkers involved in the progression of osteoarthritis (OA). Four OA cartilage-related microarray datasets were downloaded from the GEO database. A metabolism-related differentially co-expressed gene signature (MDCGS) associated with OA was then identified through an integrative computational approaches of Weighted Gene Co-expression Network Analysis (WGCNA) and Linear Models for Microarray Data (LIMMA) in combination with machine learning tools. The optimal gene expression and functions were additionally explored in vitro and in vivo. Molecular docking and molecular dynamics simulations (MDs) were conducted to explore the mode of binding with the drug and its role in OA. An MDCGS comprising 30 upregulated genes and 29 downregulated genes was identified. The LMO7 gene was determined to exhibit the most prominent importance score within the MDCGS, and subsequent molecular analyses confirmed the ability of LMO7 to ubiquitinate SIRT3, leading to its degradation and subsequent OA progression. Molecular docking and MDs were employed to further investigate the binding mode and stability of LMO7 and its inhibitors. The effectiveness of LM-1685, which had the best binding stability with LMO7, was verified in both in vivo and in vitro experiments. In summary the series of bioinformatics, machine learning, experimental, molecular docking, and MDs analyses performed in this study led to the identification of LMO7 as a promising target for treating OA progression. (STEP I) WGCNA and LIMMA approaches were used for the identification of Met-DCGs. (STEP II) Ninety-seven distinct machine learning-based models were used to develop a consensus Met-DCG signature (MDCGS). (STEP III) In subsequent in vitro experiments, SW1353 and ATDC5 OA cells were selected for construction and analysis of the OA modelto construct the OA model. The effect of LMO7 on OA progression was verified at the molecular and cellular levels. An SD rat OA model was constructed to explore the role of LMO7 knockout/overexpression in OA at the in vivo level. (STEP IV) Molecular docking and molecular dynamics simulations were used for further investigation of LMO7 to assess its potential as a target for the treatment of OA.

Bone metastasis remains a major cause of morbidity in estrogen receptor-positive breast cancer, with RANKL inhibitor resistance emerging as a critical clinical challenge. Nearly 40% of patients develop progressive skeletal lesions despite denosumab therapy, highlighting an urgent need to identify resistance mechanisms and alternative therapeutic strategies. We identified a RANKL-independent osteoclast activation pathway mediated by the CRKL/ circCCDC50/NFATc1 axis. Mechanistically, CRKL promoted EIF4A3-dependent circCCDC50 biogenesis, which was packaged into large oncosomes and transferred to osteoclast precursors. Nuclear circCCDC50 recruited CARM1 to epigenetically activate NFATc1 transcription, establishing a self-reinforcing loop that sustained osteolysis despite RANKL blockade. Pharmacological inhibition of CARM1 (TP-064) effectively suppressed osteoclastogenesis and bone metastasis in denosumab-resistant models. These findings revealed a targetable resistance mechanism and provided a clinically actionable strategy to overcome microenvironment-driven metastasis through dual targeting of tumor and bone niches.

The mouse is a key model in biomedical research, yet its tissue-specific glycoproteome remains incompletely characterized due to glycan complexity and microheterogeneity. Here, we present a comprehensive N-glycoproteomic atlas across 24 mouse tissues, comprising 3045 N-glycans with distinct structural features attached at 8681 glycosites on 74,277 glycopeptides and 5026 glycoproteins. Among these glycans, 2687 (88.2%) meet the high-confidence threshold through an integrative confidence-estimation framework. Overall glycan structural patterns show enormous tissue-specific diversities, acting as superior molecular signatures of tissue identity and system origins. Notably, even commonly expressed glycoproteins undergo tissue-dependent glycan remodeling, suggesting that glycosylation may fine-tune protein functions to meet specialized biological demands. These patterns are further shaped by subcellular localization, which constrains glycan variabilities across compartments. Co-occurrence network analyses also expose substructural biases and non-random microheterogeneities among glycans attached at the same glycosites. The dataset serves as a valuable database resource for advancing the structural and functional understanding of glycoproteins.

LncRNA LINC00857 (LINC00857) has been a subject of intensive research as an oncogene in several cancers, however, its significance in development, metastasis, and proliferation of pancreatic cancer is enigmatic. This study focus on the molecular mechanisms followed by LINC00857 to establish pancreatic cancer, its potential miRNA target, and how it induces migration and invasion of pancreatic cancer cells. Comparetive quantitative expression of LINC00857 in PANC-1 and ASPC-1 cells was detected through quantitative real-time PCR. Results from the experiments manifested up-regulated levels of LINC00857 and HMGA2 and downregulated levels of miR-1179, suggesting the negative correlation between LINC00857 and miR-1179. PANC-1 and ASPC-1 cells transfected with shRNAs of LINC00857 showed reduced cell proliferation, invasion, and migration, however, negative control group indicated high proliferative and migratory potential of pancreatic cancer cell lines. Potential binding sites of LINC00857 showed miR1179 as its direct target and LINC00857 as potential absorber for this miRNA, in turn increasing the expression of transcription factor HMGA2. The data suggest that LINC00857 can be positively used as a potential biomarker of pancreatic cancer and has proliferative, migratory and invasive role in PC. Downregulation of LINC00857 can reduce the proliferation and invasion of PC and can be an effective tool to treat pancreatic cancer clinically.

Understanding the mechanisms underlying Kirsten rat sarcoma (KRAS) mutation-driven development and progression of pancreatic ductal adenocarcinoma (PDAC) may facilitate the discovery of novel strategies for KRAS-mutant PDAC (KRASmut-PDAC) treatment. Here, it is reported that downregulation of arachidonate 15-lipoxygenase (ALOX15B) significantly correlated with poor outcomes in patients with KRASmut-PDAC. Mechanistically, KRASmut/ERK1-elicited phosphorylation of ABHD17C promotes depalmitoylation and membrane-to-cytoplasm translocation of ALOX15B, facilitating proteasome-dependent degradation of ALOX15B via interaction with the E3 ligase complex CUL4/DDB1/DCAF10. Notably, treatment with methyl protodioscin (MPD), a steroid saponin primarily purified from polygonatum sibiricum rhizome, restored the S-palmitoylation and membrane location of ALOX15B via disruption of the ABHD17C/ALOX15B interaction, consequently resulting in significant inhibition of growth rate of patient-derived KRASmut-PDAC organoids in vitro and KRASmut-PDAC-formed tumor in vivo via induction of ferroptosis. Therefore, these findings unveil a prominent role of ferroptosis evasion in KRASmut-PDAC progression and highlight the potential of targeting KRAS/ERK1/ABHD17C/ALOX15B axis in KRASmut-PDAC treatment.

S1. BASP1 downregulation is associated with poor prognosis in glioma patients.S2. Low expression of BASP1 is associated with poor prognosis in CGGA dataset.S3. Dysregulation of BASP1 alters chemoresistance of glioma cells to TMZ treatment in vitro.S4. BASP1 dysregulation has no effect on the rate of glioma cell growth in vivo.S5. Dysregulation of BASP1 alters chemoresistance to TMZ treatment in glioma cells in vivo.S6. BASP1 silencing activates NF-κB signaling in glioma cells.S7. FBXO32 expression correlates with NF-κB signaling.S8. BXO32 expression positively correlates with MGMT expression.S9. FBXO32 is associated with poor prognosis of glioma patients.S10. WDR5/MLL upregulates FBXO32 epigenetically.S11. Combined OICR-9429 sensitizes BASP1-silenced glioma cells to TMZ in vivo.Supplementary Table S1. Clinicopathological characteristics of studied patients and BASP1 expression in gliomas.Supplementary Table S2. Correlation between the clinicopathological features and expression.Supplementary Table S3. Univariate and multivariate analysis of different prognostic parameters in glioma patients by Cox-regression analysis.Supplementary Table S4. Primers and Oligonucleotides used in this study.

Currently, there are no effective prevention or therapeutic methods for breast cancer bone metastasis (BC-BM), which leading to severe skeletal complications and increased mortality. Understanding the mechanisms underlying BC-BM could provide potential strategies for its prevention and treatment. In this study, we identified a new microprotein encoded by lncRNA LINC00263, which we named LINC00263-encoded protein (LINC00263-P), was significantly upregulated in bone metastatic breast cancer tissues and correlated with BC-BM. Overexpression of LINC00263 significantly promoted BC-BM, while treatment with the neutralizing anti-LINC00263-P antibody effectively inhibited BC-BM. Mechanically, the LINC00263-P binds to integrin αvβ3 for activating Src/Syk/Vav-3 axis and yes-associated protein 1 (YAP1) pathway, which enhanced osteoclastogenesis and diminishes ferroptosis in osteoclasts, thereby creating an osteolytic bone metastasis niche that fosters BC-BM. Importantly, treatment with angoroside C, an active component from the traditional Chinese medicine Scrophulariae Radix extract, effectively blocked the binding of LINC00263-P to αvβ3, thereby inhibiting abnormal osteoclastogenesis and preventing BC-BM. These findings highlight the crucial role of microprotein LINC00263-P in disrupting bone homeostasis and propose a potential molecular mechanism of BC-BM.

Background:Platinum chemotherapy, particularly cisplatin, has been the standard treatment for ovarian cancer. However, the development of resistance to cisplatin is a significant challenge during treatment. Circular RNAs (circRNAs) are a class of non-coding RNAs with a circular structure and have been implicated in regulating ferroptosis and chemoresistance. Despite the increasing recognition of circRNAs in cancer progression, the role of circASH1L in ferroptosis and cisplatin resistance in ovarian cancer remains poorly understood. Methods:RNA sequencing (RNA-seq) was utilized to identify differentially expressed circRNAs in ovarian cancer cells. Cell survival and invasion were assessed using CCK-8 and transwell assays, while apoptosis, cell cycle progression, and lipid peroxidation were analyzed by flow cytometry. Levels of GSH, MDA, and iron ions were measured using appropriate kits. qRT-PCR and Western blot analyses were performed to evaluate the expression of relevant RNAs and proteins. The clinical relevance of circASH1L/miR-515-5p/CDCA7 axis in ovarian cancer patients was analyzed using public datasets. Molecular interactions were confirmed through dual-luciferase reporter assays, RNA immunoprecipitation (RIP), and co-immunoprecipitation (Co-IP). In vivo, the effects of circASH1L on ferroptosis and chemoresistance were evaluated using a xenograft mouse model. Results:circASH1L expression was downregulated upon erastin treatment and significantly upregulated in cisplatin-resistant A2780/DDP and SKOV3/DDP cells. Silencing circASH1L reversed cisplatin resistance by reducing cell viability and invasion, while promoting apoptosis and ferroptosis. Mechanistically, circASH1L was found to act as a sponge for miR-515-5p, which in turn regulates the CDCA7/RRM2 axis. Rescue experiments demonstrated that inhibiting miR-515-5p or overexpressing CDCA7 blocked the effects of circASH1L silencing. Moreover, CDCA7 could interact with RRM2 and inhibit RRM2 degradation, which contributed to reducing cell cycle arrest and ferroptosis resistance. The clinical analysis showed circASH1L, and CDCA7/RRM2 expression was positive correlated with drug resistance and worse survival rate, while miR-515-5p expression was on the contrary. In vivo, silencing circASH1L enhanced cisplatin sensitivity by inducing ferroptosis. Conclusion:Our study demonstrates that silencing circASH1L alleviates cisplatin resistance in ovarian cancer cells. The underlying mechanism involves the upregulation of miR-515-5p, which targets the CDCA7/RRM2 axis, leading to cell cycle modulation and the induction of ferroptosis. Targeting the circASH1L/miR-515-5p/CDCA7 pathway offers new insights into the relationship between ferroptosis and chemoresistance, presenting a promising strategy to overcome chemoresistance in ovarian cancer.

BACKGROUND:Bone metastasis is a prevalent and severe complication of breast cancer, with limited effective preventive or therapeutic strategies. Recently, circular RNA-targeted therapeutics have shown considerable promise in cancer treatment; yet their application for breast cancer-bone metastases remain infrequent. Comprehending the mechanisms underlying breast cancer-bone metastasis could provide possible targets in the future. METHODS:The biological characteristics of circRHBDD1(4,5) were validated via Sanger sequencing, RNase R, and actinomycin D treatment, and its expression was further validated using in situ hybridization in breast cancer tissues. The impact of circRHBDD1(4,5) in bone-metastatic niche formation and bone metastasis was investigated utilizing osteoclastogenesis bone resorption pit assays and xenografted tumor models. Additionally, the mechanism underlying circRHBDD1(4,5)-mediated CCL2 mRNA stability was investigated using RNA pull-down, RNA immunoprecipitation, and enzyme-linked immunosorbent assays. RESULTS:CircRHBDD1(4,5) was significantly elevated (P < 0.001) in bone-tropic metastatic breast cancer cells and bone-metastatic breast cancer tissues, which significantly enhanced osteoclastogenesis and induced the formation of bone metastatic niches by upregulating the chemokine CCL2. Mechanistically, circRHBDD1(4,5) directly interacted with CCL2 mRNA, whose expression was significantly positively correlated with immune cell infiltration and breast cancer-bone metastasis, and increased its stability and translation by recruiting the RNA-binding protein ELAVL1. Finally, treatment with locked nucleic acid (LNA) oligonucleotides, which targeted circRHBDD1(4,5) on CCL2 mRNA binding sites, namely LNA-based CMI-blockers, effectively inhibited circRHBDD1(4,5)-induced osteoclastogenesis and breast cancer-bone metastasis. CONCLUSION:We revealed a credible mechanism for circRHBDD1(4,5)-induced breast cancer-bone metastasis and hypothesized that disrupting circRHBDD1(4,5)-CCL2 mRNA interactions could be a promising strategy for treating breast cancer bone metastases.

Breast cancer brain metastasis (BCBM) remains fatal with elusive mechanisms. Here, we unveil the first circRNA m5C methylation landscape in BCBM through MeRIP-seq (methylated RNA immunoprecipitation next-generation sequencing) identifying 7465 BCBM-specific m5C peaks versus 5929 in primary breast cancer (BC). A total of 48 hypermethylated and 128 hypomethylated m5C sites in BCBM (231-BR) were identified compared to BC. Bioinformatics enrichment analysis revealed hypermethylated circRNAs enriched in ERBB/VEGF signaling pathways. Among 8 validated differentially methylated circRNAs, hsa_circ_0004516 was consistently upregulated in BCBM tissues/cells and exhibited NSUN2-dependent m5C modification. Mechanistically, NSUN2-mediated m5C methylation enhanced hsa_circ_0004516 stability, evidenced by significantly shortened half-life upon NSUN2 depletion. Crucially, catalytic mutant NSUN2 (C271A/C321A) abolished this effect. Functional assays demonstrated that hsa_circ_0004516 knockdown in 231-BR cells suppressed proliferation, migration, and invasion by reducing p-AKT (Ser473) levels. The AKT activator SC79 reversed these phenotypic impairments, definitively linking hsa_circ_0004516-driven metastasis to AKT signaling activation. Our study establishes the NSUN2-m5C-hsa_circ_0004516-AKT axis as a novel therapeutic target and biomarker for BCBM.

OBJECTIVE:Migrasomes, an emerging class of migration-facilitating membranous extracellular vesicles, remain largely uncharted in the intricate landscape of tumor metastasis. This study aimed to illuminate the roles and mechanisms underlying cancer cell-derived migrasomes in breast cancer brain metastasis (BCBM). METHODS:Migrasomes were isolated and purified from BCBM cells (231-BR) and non-specific organotropic parental counterparts (MDA-MB-231), specifically designated as Mig-BCBM and Mig-BC, respectively. The role of Mig-BCBM in BCBM was investigated using an in vitro endothelial cell layer permeability model and a BCBM mouse model. The regulatory mechanism underlying Mig-BCBM was assessed using RT-qPCR, western blotting, immunofluorescence, ex vivo fluorescence imaging, and a series of rescue experiments. RESULTS:Mig-BCBM potently augmented the permeability of vascular endothelial layers, which facilitated the efficient migration of 231-BR cells across endothelial barriers in vitro. The administration of Mig-BCBM significantly disrupted the blood-brain barrier (BBB) and accelerated BCBM progression in vivo, as evidenced in mouse models, compared to the Mig-BC and control groups. Mechanistically, Mig-BCBM harbored ATF6, a critical transducer of endoplasmic reticulum (ER) stress. Upon internalization into hCMEC/D3 cells, ATF6 elicited robust ER stress responses, culminating in downregulation of ZO-1 and VE-cadherin. Digital PCR analysis disclosed significant upregulation of ATF6 in serum migrasomes derived from BCBM patients compared to migrasomes from breast cancer patients and healthy individuals. CONCLUSIONS:This study uncovered a pivotal role of cancer cell-derived in BCBM by harnessing ATF6-mediated ER stress to disrupt the BBB and promote metastasis, suggesting novel diagnostic and therapeutic strategies targeting migrasomes and migrasome cargo.

[This corrects the article DOI: 10.3389/fonc.2025.1556311.].

[This retracts the article DOI: 10.3892/etm.2019.7260.].

Breast cancer is a leading cause of cancer-related mortality, with tumor heterogeneity and drug resistance posing significant challenges to treatment. We integrated single-cell RNA sequencing, spatial transcriptomics, and bulk RNA-seq deconvolution to analyze BRCA samples. Our analysis identified 15 major cell clusters, including neoplastic epithelial, immune, stromal, and endothelial populations. Notably, low-grade tumors showed enriched subtypes, such as CXCR4+ fibroblasts, IGKC+ myeloid cells, and CLU+ endothelial cells, with distinct spatial localization and immune-modulatory functions. These subtypes were paradoxically linked to reduced immunotherapy responsiveness, despite their association with favorable clinical features. High-grade tumors exhibited reprogrammed intercellular communication, with expanded MDK and Galectin signaling. Bulk RNA-seq deconvolution further supported the prognostic significance of low-grade-enriched subtypes. Our findings highlight the heterogeneity of the tumor microenvironment and provide new insights into immune evasion and therapeutic resistance in breast cancer.

Inducing lipid peroxidation-dependent ferroptosis is a promising anticancer strategy; however, the development of resistance poses a considerable challenge. This study identifies peroxiredoxin 6 (PRDX6) as a crucial modulator of glutathione peroxidase 4 (GPX4), affecting its localization and functional roles, thus contributing to ferroptosis resistance. PRDX6, endowed with phospholipase A2 activity, catalyzes the conversion of peroxy-phospholipids to lysophospholipids and oxidized fatty acids. Through targeted structural mutations and biochemical analyses, we demonstrate that PRDX6 binds to GPX4 via a C47 disulfide bond, facilitating GPX4’s membrane translocation and enhanced production of hydroxy fatty acids. Combining the inhibition of PRDX6 with ferroptosis inducers increases lipid peroxidation, effectively suppressing tumor growth in liver and ovarian cancer mouse models, including patient-derived models. Furthermore, high PRDX6 expression correlates with shorter progression-free survival across multiple human cancer types. Collectively, our findings delineate a PRDX6-dependent mechanism in ferroptosis defense, offering new perspectives for targeted cancer therapy.

Chemoresistance remains a major obstacle in prostate cancer therapy. This study demonstrates that high extracellular matrix stiffness promotes chemoresistance by disrupting mitochondrial-nuclear communication. Culturing prostate cancer cells on polyacrylamide hydrogels of varying stiffness revealed that a high-stiffness environment promotes mitochondrial fusion and enhances function. Mechanistic investigations revealed that high matrix stiffness activates YAP, leading to dysregulation of the Hippo signaling pathway, which subsequently upregulates the expression of OPA1 and induces mitochondrial fusion. This fusion triggers a reprogramming of glutamine metabolism. The resulting metabolite, α-ketoglutarate, activated DNA demethylases TET1 and TET3, causing epigenetic modifications of YAP target genes and further exacerbating Hippo pathway dysregulation. Together, this establishes a YAP-OPA1-TET1/3-mediated positive feedback loop between the nucleus and mitochondria that drives drug resistance. Crucially, targeting OPA1 disrupted this loop and reversed stiffness-induced chemoresistance. These findings reveal a novel mitochondrial-nuclear communication, offering new insights for overcoming chemoresistance in prostate cancer.

Background:Tertiary lymphoid structures (TLS), consisting of T cell zones, B cell follicles, and germinal centers (GCs), are ectopic lymphoid tissue that form within non-lymphoid tissue. It has recently become a focus of attention. The TLS serve as an effective site for generating an anti-tumor inflammatory response by infiltrating immune cells, especially plasma cells. Thus, we aimed to explore the role of both TLS and plasma cells in influencing the prognosis of lung adenocarcinoma (LUAD). Methods:Single-cell RNA sequencing (scRNA-seq) data were obtained from the Gene Expression Omnibus (GEO) database, and bulk RNA-seq data and clinical information were downloaded from The Cancer Genome Atlas (TCGA) database. Seurat R package was used to process scRNA-seq data and identify clusters by the marker genes with Kaplan-Meier (KM) curves plotted to predict the prognosis. Finally, hematoxylin and eosin (H&E) staining and multiplex immunofluorescence analysis were conducted to corroborate our suspicions. Results:Seven clusters were identified in LUAD based on scRNA-seq data, with the number of B cells differing significantly between early and advanced cohorts. The plasma cells were also increased in advanced lung cancer (LC) and the number of TLS was significantly related to tumor stage. Then, via KM method, we confirmed that both plasma cells and TLS were associated with patient outcomes. Finally, H&E staining and multiplex immunofluorescence analysis verified the correlation between the two. Conclusions:Plasma cells and TLS can effectively predict the prognosis of LUAD. In the tumor microenvironment (TME) of advanced tumors, plasma cells might be in a state of functional exhaustion. Comprehensive characterization of TLS and corresponding B‑cell pathways may help to activate the function of plasma cells and provide new strategies for cancer treatment.