Neutrophil CD64 index as a potential blood biomarker for the diagnosis of neurosyphilis in secondary and tertiary syphilis: A retrospective study.

Objective: To examine the correlation of neutrophil CD64 (nCD64) index with neurosyphilis (NS) across different stages of syphilis. Methods: A total of 1243 syphilis patients at different stages (344 of primary, 385 of secondary, and 514 of tertiary) included in this study were divided into NS and non-NS (NNS). Correlations of nCD64 index with currently used syphilis biomarkers were explored using Spearman correlation test. Relationships between nCD64 index and NS at different stages were investigated by stratified analysis and restricted cubic spline model. The diagnostic performance of nCD64 index for NS was assessed by receiver operating characteristic (ROC) curve. Results: Significant statistical correlations of nCD64 index with cerebrospinal fluid (CSF) NS indicators were found in secondary and tertiary syphilis. Increased nCD64 index was associated with increased risk of NS in secondary and tertiary syphilis. ROC analysis values further confirmed the diagnostic potential of nCD64 index for NS. Marked decrease of nCD64 index was observed in NS patients after effective antisyphilitic treatments. Conclusions: The nCD64 index may help to the diagnosis of NS in secondary and tertiary syphilis.

Exploring the Role of DNA Methylation Located in Cuproptosis-Related Genes: Implications for Prognosis and Immune Landscape in Hepatocellular Carcinoma.

BACKGROUND: Copper dysregulation has been linked to liver disease, cardiac dysfunction, neuropathy, and anemia. Previous investigations have been undertaken to demonstrate the impact of cuproptosis-related genes (CRGs) on the poor prognosis of hepatocellular carcinoma (HCC), while the prognostic significance and beneath molecular basis of DNA-methylation sites located in CRGs remain unknown. This study aims to identify CRG-located DNA-methylation sites linked to patient prognosis and establish a novel prognostic biomarkers combination for CRG-located DNA-methylation signature. METHODS: The prognostic biomarkers combination was established through multivariate-Cox-regression after CRG-located DNA-methylation sites tied to the outcome of patients emerged by univariate-Cox-regression. The correlation between signature and immune cell infiltration levels, immune-checkpoint-associated genes was analyzed using spearman correlation and the difference was contrasted between different groups utilizing the Mann-Whitney-U test. Real-time quantitative methylation-specific polymerase chain reaction (RT-qMSP) was used to identify gene methylation. RESULTS: A novel prognostic biomarkers combination for CRG-located DNA-methylation signature was established. Subsequently, the independence of this methylation signature from clinical features and its correlation with immune infiltrative and immune checkpoints in HCC were also investigated. DNA methylation alterations can influence the onset, development, and treatment of various tumors by regulating the transcription of corresponding genes. Our analysis found that cg05706061 contained in prognosis signature was located in the promoter region of the cuproptosis-related gene SLC31A2. The DNA-methylation level of cg05706061 demonstrated significantly different between tumor and normal tissue, and significantly correlated with the expression of SLC31A2. We further investigated the promoter methylation status of SLC31A2 by qMSP, the result showed that the DNA-methylation level of SLC31A2 in HCC cell lines were significantly decreased compared with normal liver cells. CONCLUSIONS: Our findings reveal possible mechanisms of CRG-located DNA-methylation on the advancement of HCC and offers new perspectives for prognostic assessment and treatment options.

SNORA56-mediated pseudouridylation of 28 S rRNA inhibits ferroptosis and promotes colorectal cancer proliferation by enhancing GCLC translation.

BACKGROUND: Colorectal cancer (CRC) is one of the most common malignancies and is characterized by reprogrammed metabolism. Ferroptosis, a programmed cell death dependent on iron, has emerged as a promising strategy for CRC treatment. Although small nucleolar RNAs are extensively involved in carcinogenesis, it is unclear if they regulate ferroptosis during CRC pathogenesis. METHODS: The dysregulated snoRNAs were identified using published sequencing data of CRC tissues. The expression of the candidate snoRNAs, host gene and target gene were assessed by real-time quantitative PCR (RT-qPCR), fluorescence in situ hybridization (FISH), immunohistochemistry (IHC) and western blots. The biological function of critical molecules was investigated using in vitro and in vivo strategies including Cell Counting Kit-8 (CCK8), colony formation assay, flow cytometry, Fe2+/Fe3+, GSH/GSSG and the xenograft mice models. The ribosomal activities were determined by polysome profiling and O-propargyl-puromycin (OP-Puro) assay. The proteomics was conducted to clarify the downstream targets and the underlying mechanisms were validated by IHC, Pearson correlation analysis, protein stability and rescue assays. The clinical significance of the snoRNA was explored using the Cox proportional hazard model, receiver operating characteristic (ROC) and survival analysis. RESULTS: Here, we investigated the SNORA56, which was elevated in CRC tissues and plasma, and correlated with CRC prognosis. SNORA56 deficiency in CRC impaired proliferation and triggered ferroptosis, resulting in reduced tumorigenesis. Mechanistically, SNORA56 mediated the pseudouridylation of 28 S rRNA at the U1664 site and promoted the translation of the catalytic subunit of glutamate cysteine ligase (GCLC), an indispensable rate-limiting enzyme in the biosynthesis of glutathione, which can inhibit ferroptosis by suppressing lipid peroxidation. CONCLUSIONS: Therefore, the SNORA56/28S rRNA/GCLC axis stimulates CRC progression by inhibiting the accumulation of cellular peroxides, and it may provide biomarker and therapeutic applications in CRC.

Northern Shanghai Study II: systematic assessment and management of early organ damage and its role in preventing and reducing cardiovascular risk-protocol of a prospective study.

INTRODUCTION: Cardiovascular diseases are the leading cause of death and disease burden in China. However, there is a lack of prospective cohort studies suitable for evaluating early organ damage and its role in preventing and reducing cardiovascular risk among Chinese residents. This study intends to establish the first database based on the phenotypes of all early structural and functional damage of cardiovascular organs in Chinese population. Moreover, a digital follow-up mechanism will be formed, a prospective population cohort will be established, a biological sample bank for early cardiovascular organ damage will be established, and an intervention and management system for early damage of cardiovascular organs will be explored. METHODS AND ANALYSIS: This study is a prospective cohort study built on the foundation of the Northern Shanghai Study I. People aged 18-75 years are enrolled. After the recruitment, first, corresponding physical measurements and clinical examinations are conducted to collect cardiovascular risk factors and establish the demographic baseline of the study population. Next, the latest equipment is used to evaluate early structural and functional cardiovascular organ damage including heart, macrovessels, microcirculation, renal function and fundus. Meanwhile, the blood, urine, faeces and other biological samples of participants are collected to establish the cardiometabolic and gut microbiota analysis databases. The population is followed up every 2 years. Comprehensive assessment of early organ damage will be used to predict cardiovascular risk, guide people to change lifestyles to achieve early prevention and provide corresponding treatment recommendations. ETHICS AND DISSEMINATION: This study was approved by the Shanghai Tenth People's Hospital Institutional Review Board. All participants signed a written consent form. The results of this study will be disseminated in peer-reviewed journals. Ethics approval: SHYS-IEC-5.0/22k148/P01. TRIAL REGISTRATION NUMBER: NCT05435898.

Anti-ferroptotic PRKAA2 serves as a potential diagnostic and prognostic marker for hepatoblastoma.

Background: The incidence rate of hepatoblastoma (HB), which is the most prevalent malignant tumour among children, rises each year. According to recent studies, a number of neoplastic disorders and ferroptosis are intimately connected. This study aims to identify key ferroptosis-related genes in HB and explore new directions for the diagnosis and treatment of HB. Methods: Differentially expressed ferroptosis-related genes were identified using the Gene Expression Omnibus datasets. The functional annotation of candidate genes was evaluated through Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. Machine learning and receiver operating characteristic (ROC) curves revealed protein kinase AMP-activated catalytic subunit alpha 2 (PRKAA2), tribbles homolog 2 (TRIB2), and liver-type glutaminase (GLS2) as potential diagnostic genes of HB. By using quantitative reverse transcription polymerase chain reaction (qRT-PCR) and immunohistochemistry, relative expression of PRKAA2 was examined. The effect of PRKAA2 on proliferation, apoptosis, and ferroptosis of HB cells was verified in vitro and in vivo. Fisher's exact test was used to evaluate the clinical significance of PRKAA2 in HB. Results: The prognostic indicators had a substantial correlation with PRKAA2 expression, which rose dramatically in HB tissues. PRKAA2 promotes proliferation and inhibits ferroptosis in HB cells. PRKAA2 plays a role in ferroptosis by regulating hypoxia-inducible factor 1α (HIF-1α) and transferrin receptor 1 (TFR1). Conclusions: PRKAA2 functions as a tumor-promoting factor in HB by promoting cell proliferation and prohibiting ferroptosis. Ferroptosis-related genes PRKAA2 is a potential diagnostic and prognostic marker for HB as well as a novel therapeutic target in the future.

Correction: Li et al. m6A mRNA Methylation Regulates LKB1 to Promote Autophagy of Hepatoblastoma Cells through Upregulated Phosphorylation of AMPK. Genes 2021, 12, 1747.

In the original publication [...].

SNORD11B-mediated 2'-O-methylation of primary let-7a in colorectal carcinogenesis.

Evidence indicates that small nucleolar RNAs (snoRNAs) participate in tumorigenesis and development and could be promising biomarkers for colorectal cancer (CRC). Here, we examine the profile of snoRNAs in CRC and find that expression of SNORD11B is increased in CRC tumor tissues and cell lines, with a significant positive correlation between SNORD11B expression and that of its host gene NOP58. SNORD11B promotes CRC cell proliferation and invasion and inhibits apoptosis. Mechanistically, SNORD11B promotes the processing and maturation of 18 S ribosomal RNA (rRNA) by mediating 2'-O-methylated (Nm) modification on the G509 site of 18 S rRNA. Intriguingly, SNORD11B mediates Nm modification on the G225 site of MIRLET7A1HG (pri-let-7a) with a canonical motif, resulting in degradation of pri-let-7a, inhibition of DGCR8 binding, reduction in mature tumor suppressor gene let-7a-5p expression, and upregulation of downstream oncogene translation. SNORD11B performs comparably to CEA and CA199 in diagnosing CRC. High expression of SNORD11B is significantly correlated with a more advanced TNM stage and lymph node metastasis, which indicates poor prognosis.

Biological effect abundance analysis of hemolytic pathogens based on engineered biomimetic sensor.

Conventional pathogen detection strategies based on the molecular structure or chemical characteristics of biomarkers can only provide the "physical abundance" of microorganisms, but cannot reflect the "biological effect abundance" in the true sense. To address this issue, we report an erythrocyte membrane-encapsulated biomimetic sensor cascaded with CRISPR-Cas12a (EMSCC). Taking hemolytic pathogens as the target model, we first constructed an erythrocyte membrane-encapsulated biomimetic sensor (EMS). Only hemolytic pathogens with biological effects can disrupt the erythrocyte membrane (EM), resulting in signal generation. Then the signal was amplified by cascading CRISPR-Cas12a, and more than 6.67 × 104-fold improvement in detection sensitivity compared to traditional erythrocyte hemolysis assay was achieved. Notably, compared with polymerase chain reaction (PCR) or enzyme linked immunosorbent assay (ELISA)-based quantification methods, EMSCC can sensitively respond to the pathogenicity change of pathogens. For the detection of simulated clinical samples based on EMSCC, we obtained an accuracy of 95% in 40 samples, demonstrating its potential clinical value.

Alternative Splicing of lncRNAs From SNHG Family Alters snoRNA Expression and Induces Chemoresistance in Hepatoblastoma.

BACKGROUND & AIMS: Hepatoblastoma (HB) is a common pediatric malignant liver tumor that is characterized by a low level of genetic mutations. Alternative splicing (AS) has been shown to be closely associated with cancer progression, especially in tumors with a low mutational burden. However, the role of AS in HB remains unknown. METHODS: Transcriptome sequencing was performed on 5 pairs of HB tissues and matched non-tumor tissues to delineate the AS landscape in HB. AS events were validated in 92 samples from 46 patients. RNA pull-down and RNA immunoprecipitation assays were carried out to identify splicing factors that regulate the AS of small nucleolar RNA host genes (SNHG). Patient-derived organoids (PDOs) were established to investigate the role of the splicing factor polyadenylate-binding nuclear protein 1 (PABPN1). RESULTS: This study uncovered aberrant alternative splicing in HB, including lncRNAs from SNHG family that undergo intron retention in HB. Further investigations revealed that PABPN1, a significantly upregulated RNA binding protein, interacts with splicing machinery in HB, inducing the intron retention of these SNHG RNAs and the downregulation of intronic small nucleolar RNAs (snoRNAs). Functionally, PABPN1 acts as an oncofetal splicing regulator in HB by promoting cell proliferation and DNA damage repair via inducing the intron retention of SNHG19. Knock-down of PABPN1 increases the cisplatin sensitivity of HB PDOs. CONCLUSIONS: Our findings revealed the role of intron retention in regulating snoRNA expression in hepatoblastoma, explained detailed regulatory mechanism between PABPN1 and the intron retention of SNHG RNAs, and provided insight into the development of new HB treatment options.

Identification of key enzalutamide-resistance-related genes in castration-resistant prostate cancer and verification of RAD51 functions.

Patients with castration-resistant prostate cancer (CRPC) often develop drug resistance after treatment with enzalutamide. The goal of our study was to identify the key genes related to enzalutamide resistance in CRPC and to provide new gene targets for future research on improving the efficacy of enzalutamide. Differential expression genes (DEGs) associated with enzalutamide were obtained from the GSE151083 and GSE150807 datasets. We used R software, the DAVID database, protein-protein interaction networks, the Cytoscape program, and Gene Set Cancer Analysis for data analysis. The effect of RAD51 knockdown on prostate cancer (PCa) cell lines was demonstrated using Cell Counting Kit-8, clone formation, and transwell migration experiments. Six hub genes with prognostic values were screened (RAD51, BLM, DTL, RFC2, APOE, and EXO1), which were significantly associated with immune cell infiltration in PCa. High RAD51, BLM, EXO1, and RFC2 expression was associated with androgen receptor signaling pathway activation. Except for APOE, high expression of hub genes showed a significant negative correlation with the IC50 of Navitoclax and NPK76-II-72-1. RAD51 knockdown inhibited the proliferation and migration of PC3 and DU145 cell lines and promoted apoptosis. Additionally, 22Rv1 cell proliferation was more significantly inhibited with RAD51 knockdown than without RAD51 knockdown under enzalutamide treatment. Overall, six key genes associated with enzalutamide resistance were screened (RAD51, BLM, DTL, RFC2, APOE, and EXO1), which are potential therapeutic targets for enzalutamide-resistant PCa in the future.

O-GlcNAcylated LARP1 positively regulated by circCLNS1A facilitates hepatoblastoma progression through DKK4/ß-catenin signalling.

BACKGROUND: Accumulating studies have shown that La-related protein 1 (LARP1) is involved in the occurrence and development of various tumours. However, the expression pattern and biological role of LARP1 in hepatoblastoma (HB) remain unclear so far. METHODS: LARP1 expression level in HB and adjacent normal liver tissues was analysed by qRT-PCR, Western blotting and immunohistochemistry assays. The prognostic significance of LARP1 was evaluated by Kaplan-Meier method and multivariate Cox regression analysis. In vitro and in vivo functional assays were implemented to clarify the biological effects of LARP1 on HB cells. Mechanistically, the regulatory roles of O-GlcNAcylation and circCLNS1A in LARP1 expression were investigated by co-immunoprecipitation (co-IP), immunofluorescence, RNA immunoprecipitation (RIP), RNA pull-down and protein stability assays. Moreover, RNA-sequencing, co-IP, RIP, mRNA stability and poly(A)-tail length assays were performed to investigate the association between LARP1 and DKK4. The expression and diagnostic significance of plasma DKK4 protein in multi-centre cohorts were evaluated by ELISA and ROC curves. RESULTS: LARP1 mRNA and protein levels were remarkably elevated in HB tissues and associated with worse prognosis of HB patients. LARP1 knockdown abolished cell proliferation, triggered cell apoptosis in vitro as well as prohibited tumour growth in vivo, whereas LARP1 overexpression incited HB progression. Mechanistically, O-GlcNAcylation of LARP1 Ser672 by O-GlcNAc transferase strengthened its binding to circCLNS1A and then protected LARP1 from TRIM-25-mediated ubiquitination and proteolysis. LARP1 upregulation subsequently led to DKK4 mRNA stabilisation by competitively interacting with PABPC1 to prevent DKK4 mRNA from B-cell translocation gene 2-dependent deadenylation and degradation, thus facilitating ß-catenin protein expression and nuclear import. CONCLUSION: This study indicates that upregulated protein level of O-GlcNAcylated LARP1 mediated by circCLNS1A promotes the tumorigenesis and progression of HB through LARP1/DKK4/ß-catenin axis. Hence, LARP1 and DKK4 are promising therapeutical target and diagnostic/prognostic plasma biomarker for HB.

Throwing and manipulating and cheating with a DNA nano-dice.

Artificial molecular machines have captured the imagination of researchers, given their clear potential to mimic and influence human life. Key to behavior simulation is to reproduce the specific properties of physical or abstract systems. Dice throwing, as a stochastic model, is commonly used for result judgment or plan decision in real life. In this perspective we utilize DNA cube framework for the design of a dice device at the nanoscale to reproduce probabilistic events in different situations: equal probability, high probability, and low probability. We first discuss the randomness of DNA cube, or dice, adsorbing on graphene oxide, or table, and then explore a series of events that change the probability through the way in which the energy released from entropy-driven strand displacement reactions or changes in intermolecular forces. As such, the DNA nano-dice system provides guideline and possibilities for the design, engineering, and quantification of behavioral probability simulation, a currently emerging area of molecular simulation research.

Lantern-shaped flexible RNA origami for Smad4 mRNA delivery and growth suppression of colorectal cancer.

mRNA delivery has shown high application value in the treatment of various diseases, but its effective delivery is still a major challenge at present. Herein, we propose a lantern-shaped flexible RNA origami for mRNA delivery. The origami is composed of a target mRNA scaffold and only two customized RGD-modified circular RNA staples, which can compress the mRNA into nanoscale and facilitate its endocytosis by cells. In parallel, the flexible structure of the lantern-shaped origami allows large regions of the mRNA to be exposed and translated, exhibiting a good balance between endocytosis and translation efficiency. The application of lantern-shaped flexible RNA origami in the context of the tumor suppressor gene, Smad4 in colorectal cancer models demonstrates promising potential for accurate manipulation of protein levels in in vitro and in vivo settings. This flexible origami strategy provides a competitive delivery method for mRNA-based therapies.

SNORA14A inhibits hepatoblastoma cell proliferation by regulating SDHB-mediated succinate metabolism.

Hepatoblastoma (HB) is the most common paediatric liver malignancy. Dysregulation of small nucleolar RNAs (snoRNAs) is a critical inducer of tumour initiation and progression. However, the association between snoRNAs and HB remains unknown. Here, we conducted snoRNA expression profiling in HB by snoRNA sequencing and identified a decreased level of SNORA14A, a box H/ACA snoRNA, in HB tissues. Low expression of SNORA14A was correlated with PRETEXT stage and metastasis in patients. Functionally, overexpression of SNORA14A suppressed HB cell proliferation and triggered cell apoptosis and G2/M phase arrest. Mechanistically, SNORA14A overexpression promoted the processing and maturation of the 18 S ribosomal RNA (rRNA) precursor to increase succinate dehydrogenase subunit B (SDHB) protein levels. In accordance with SNORA14A downregulation, SDHB protein expression was significantly reduced in HB tissues and cells, accompanied by abnormal accumulation of succinate. Overexpression of SDHB showed antiproliferative and proapoptotic effects and the capacity to induce G2/M phase arrest, while succinate dose-dependently stimulated HB cell growth. Furthermore, the inhibition of SNORA14A in HB malignant phenotypes was mediated by SDHB upregulation-induced reduction of cellular succinate levels. Therefore, the SNORA14A/18 S rRNA/SDHB axis suppresses HB progression by preventing cellular accumulation of the oncometabolite succinate and provides promising prognostic biomarkers and novel therapeutic targets for HB.

Sperm-like nanocarriers for ultrafast delivery of antisense DNA.

Although various nanomaterials have been designed as intracellular delivery tools, the following aspects have become obstacles to limit their development, like a complex and time-consuming synthesis process, as well as relatively limited application areas (i.e. biosensing or cell imaging). Here, we developed a novel nano-delivery system called "nano-sperm" with low cytotoxicity and high biocompatibility. In this system, we used DNA oligonucleotides as a backbone to synthesize a nanostructure with silver nanoclusters in the head and functional fragments in the tail, which is shaped like a sperm, to achieve dual functions of ultrafast delivery and imaging/therapy. As a model, we analyzed the possibility of the "nano-sperm" carrying DNA with different structures for imaging or survivin-asDNA for tumor therapy. Therefore, this work reports a novel bifunctional high-speed delivery vehicle, which successfully fills the gap in the field of tumor therapy using DNA-templated nanoclusters as a delivery vehicle.

Highly selective titanium (IV)-immobilized O-phospho-L-tyrosine modified magnetic nanoparticles for the enrichment of intact phosphoproteins.

Phosphorylation is one of the most important protein post-translational modifications, which possesses dramatic regulatory effects on the function of proteins. In consideration of the low abundance and low stoichiometry of phosphorylation and non-specific signal suppression, efficient capture of the phosphoproteins from complex biological samples is critical to meet the need for protein profiling. In this work, a facile preparation of titanium (IV)-immobilized O-phospho-L-tyrosine modified magnetic nanoparticles was developed for the enrichment of intact phosphoproteins. The prepared magnetic nanoparticles were characterized by various instruments and had a spherical shape with an average diameter of 300 nm. The adsorption isotherms were investigated and the maximum capacity for ß-casein was calculated to be 961.5 mg/g. Standard protein mixtures and biological samples (non-fat milk and human serum) were selected to test the enrichment performance. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis demonstrated the excellent enrichment performance with high selectivity. With the superparamagnetic property, titanium (IV)-immobilized O-phospho-L-tyrosine modified magnetic nanoparticles were convenient for the practical application and clinical promotion, thus having a promising prospect in the field of phosphoprotein research.

Characteristics of Prognostic Programmed Cell Death-Related Long Noncoding RNAs Associated With Immune Infiltration and Therapeutic Responses to Colon Cancer.

Programmed cell death (PCD) plays an important role in the onset and progression of various cancers. The molecular events surrounding the occurrence of abnormally expressed long noncoding RNAs (lncRNAs) leading to colon cancer (CC) have become a focus. We comprehensively evaluated the roles of PCD-related lncRNAs in the clinical management of CC and their immune responses. Therefore, we screened 41 prognostic PCD-related lncRNAs in The Cancer Genome Atlas database using co-expression analysis and assigned patients to groups according to the results of cluster analysis. The immune response and functions of cluster 2 were substantially suppressed, which might explain the poor prognosis in this group. A prognostic model comprising eight PCD-related lncRNAs was developed, and its effectiveness was verified using an external database. High-and low-risk groups had different epigenetic modifications and changes in immune cell infiltration. Patients in the high-risk group were resistant to immunotherapy and various chemotherapeutic drugs. Studies in vitro and in vivo further confirmed a carcinogenic role of the lncRNA U62317.4. Our findings of the prognostic value of PCD-related lncRNAs revealed their important roles in immune response disorders, thus providing valuable insights into the clinical management and molecular mechanisms of CC.

The N6-methyladenosine modification enhances ferroptosis resistance through inhibiting SLC7A11 mRNA deadenylation in hepatoblastoma.

BACKGROUND: Solute carrier family 7 member 11 (SLC7A11) is overexpressed in multiple human tumours and functions as a transporter importing cystine for glutathione biosynthesis. It promotes tumour development in part by suppressing ferroptosis, a newly identified form of cell death that plays a pivotal role in the suppression of tumorigenesis. However, the role and underlying mechanisms of SLC7A11-mediated ferroptosis in hepatoblastoma (HB) remain largely unknown. METHODS: Reverse transcription quantitative real-time PCR (RT-qPCR) and western blotting were used to measure SLC7A11 levels. Cell proliferation, colony formation, lipid reactive oxygen species (ROS), MDA concentration, 4-HNE, GSH/GSSG ratio and cell death assays as well as subcutaneous xenograft experiments were used to elucidate the effects of SLC7A11 in HB cell proliferation and ferroptosis. Furthermore, MeRIP-qPCR, dual luciferase reporter, RNA pulldown, RNA immunoprecipitation (RIP) and RACE-PAT assays were performed to elucidate the underlying mechanism through which SLC7A11 was regulated by the m6A modification in HB. RESULTS: SLC7A11 expression was highly upregulated in HB. SLC7A11 upregulation promoted HB cell proliferation in vitro and in vivo, inhibiting HB cell ferroptosis. Mechanistically, SLC7A11 mRNA exhibited abnormal METTL3-mediated m6A modification, which enhanced its stability and expression. IGF2 mRNA-binding protein 1 (IGF2BP1) was identified as the m6A reader of SLC7A11, enhancing SLC7A11 mRNA stability and expression by inhibiting SLC7A11 mRNA deadenylation in an m6A-dependent manner. Moreover, IGF2BP1 was found to block BTG2/CCR4-NOT complex recruitment via competitively binding to PABPC1, thereby suppressing SLC7A11 mRNA deadenylation. CONCLUSIONS: Our findings demonstrated that the METTL3-mediated SLC7A11 m6A modification enhances HB ferroptosis resistance. The METTL3/IGF2BP1/m6A modification promotes SLC7A11 mRNA stability and upregulates its expression by inhibiting the deadenylation process. Our study highlights a critical role of the m6A modification in SLC7A11-mediated ferroptosis, providing a potential strategy for HB therapy through blockade of the m6A-SLC7A11 axis.