Ulcerative colitis (UC) is an incurable inflammatory bowel disease characterized by chronic mucosal inflammation, with a continuously increasing global prevalence. Although infrared (IR) therapy has demonstrated anti-inflammatory potential, conventional devices that can only emit single-wavelength IR often exhibit limited tissue penetration and poor suboptimal spectral overlap with mammalian absorption. Herein, we develop a broad-spectrum infrared (BSIR) device enabled with an almost defect-free graphene based radiator to deliver high output IR aligned with mammalian IR absorption spectra. In a mouse model of UC, BSIR treatment significantly alleviated disease symptoms and promoted mucosal recovery. Crucially, this study shows that BSIR radiation induces the relocation of T lymphocytes to the spleen, leading to reduced immune cell infiltration and inflammation in the colon. Gene expression analysis further reveals enhanced innate immune activity and cell regeneration in colonic tissue. Collectively, these findings demonstrate that BSIR represents a safe, noninvasive therapeutic strategy for UC. More broadly, this study highlights spectrum-matched IR irradiation as a novel modality for immune modulation, with potential translational relevance for other deep-tissue inflammatory diseases.

The advent of advanced molecular technologies, particularly the widespread use of next-generation sequencing (NGS), has revolutionized the life sciences research landscape. NGS, characterized by high throughput, specificity, and sensitivity, offers a superior alternative to traditional detection methods, particularly in the context of viral pandemics and emerging infectious diseases. It has proven indispensable not only in identifying novel therapeutic targets but also in monitoring viral resistance. This review provides a comprehensive analysis of NGS applications in infectious diseases and pathogenic microorganisms, with an emphasis on its role in rapid pathogen detection, accurate identification, interspecies transmission tracking, and resistance profiling. Through the integration of these insights, the review offers a forward-looking perspective on emerging trends and challenges, highlighting the transformative impact of these technologies on the understanding and management of infectious diseases.

N6-methyladenosine (m6A), the most abundant internal modification in eukaryotic mRNAs, plays crucial regulatory roles in carcinogenesis through post-transcriptional regulation of mRNA metabolism. Although emerging evidence highlights its significance in tumor biology, the epigenetic mechanism underlying gallbladder carcinoma (GBC) progression remains poorly characterized. In the present study, KIAA1429, a key component of the m6A methyltransferase complex, was significantly upregulated in GBC and correlated with aggressive tumor characteristics and poor patient survival. Functionally, KIAA1429 knockdown substantially impaired cellular proliferation, migration, and invasion in vitro and suppressed xenograft tumor growth in vivo. Conversely, KIAA1429 overexpression promoted malignant phenotypes in GBC. Mechanistically, an integrated analysis of MeRIP-seq and GEO data identified KIF20A as a downstream effector of KIAA1429. Further experiments demonstrated that KIAA1429 upregulates KIF20A expression. Overexpression of KIF20A partially restored the proliferation and invasion abilities of GBC cells curtailed by KIAA1429 knockdown. Taken together, our work uncovers a critical function for KIAA1429 in driving GBC progression and reveals novel mechanistic insights into m6A methylation in gallbladder carcinogenesis.

BackgroundHepatocellular carcinoma (HCC) is one of the most common malignant liver tumor with poor clinical outcomes. Accumulated evidence has demonstrated lactylation plays a vital role in the metabolic reprogramming. However the mechanisms underlying the role of lactylation in the regulation of HCC progression remain largely unknown. This study aims to construct a prognostic model based on lactylation-related metabolism genes, and further explore its prognostic significance and biological function in HCC.MethodsIn this study, a robust prognostic prediction model has been constructed employing a complex machine learning framework using public bulk RNA-seq and proteomic HCC dataset. Moreover, the clinical application of this model was explored, and its biological functions were validated using several in vitro experiments. Subsequently, we performed functional analysis, survival analysis, tumor immune microenvironment analysis and drug sensitivity to demonstrate our model's potential in translational cancer medicine.ResultsWe developed an integrative machine learning-based computational framework to generate a predictive Metabolism-related Lactylation Index (MRLI) within four independent HCC cohorts and validated its prognostic accuracy through various algorithms. Notably, compared to published gene signatures, MRLI demonstrated robust predictive capability. In addition, single-cell analysis demonstrated that the MRLI is predominantly localized within HCC cells and correlates with tumor malignancy. Mechanistically, Gene Set Enrichment Analysis (GSEA) suggested that the MRLI may be associated with cellular proliferation and metabolic reprogramming, which was further confirmed by experimental evidence. Subsequently, public spatial transcriptomics and bulk RNA-seq analysis revealing that the highly MRLI predicts a tumor immunosuppressive microenvironment, which was further verification in a cohort of 40 HCC samples by multiple immunofluorescence. Additionally, groups with highly MRLI showed decreased sensitivity to sorafenib, immune checkpoint inhibitors, and TACE, highlighting the potential of MRLI in facilitating personalized treatment strategies.ConclusionOur study has developed a novel MRLI as a predictive marker for prognosis and therapeutic outcomes in patients with HCC. These findings indicate that lactylation promotes malignant cell phenotypes and immune microenvironment remodeling partially through metabolic regulation, suggesting it as a potential clinical therapeutic target.

Hepatic fibrosis, a critical progression in liver disease, has been widely studied. While the activation of stellate cells and the accumulation of extracellular matrix components are recognized as key mechanisms, additional research is necessary to uncover further complexities. Recent investigations underscore the pivotal role of post-translational modifications (PTMs) in hepatic fibrosis. This study explores nine PTMs—methylation, acetylation, SUMOylation, Neddylation, phosphorylation, crotonylation, glycosylation, lactylation, and ubiquitination—each implicated in the pathogenesis of hepatic fibrosis. Furthermore, six classes of drugs—ACC inhibitors, ASK1 inhibitors, Akt activators, FXR agonists, PTP1B inhibitors, and HDAC inhibitors—are reviewed for their therapeutic potential in targeting PTMs to treat hepatic fibrosis.

BACKGROUND:The long non-coding RNA PVT1 (lncRNA PVT1) has been reported to act as an oncogenic regulator of several cancers. However, its expression and function in gallbladder cancer (GBC) remain largely unknown. METHODS:In situ hybridization (ISH) and quantitative real-time PCR (qPCR) were performed to detect the expression of PVT1 and miR-143 in GBC tissues and cell lines. Immunohistochemistry (IHC) assays were performed to assess the expression of the hexokinase 2 (HK2) protein. The relationships among PVT1, miR-143 and HK2 were evaluated using dual-luciferase reporter, RNA immunoprecipitation (RIP) and biotin pull-down assays. The biological functions of PVT1, miR-143 and HK2 in GBC cells were explored with cell counting kit 8 (CCK-8), 5-ethynyl-20-deoxyuridine (EdU), colony formation, transwell, wound healing and glucose metabolism assays in vitro. For in vivo experiments, a xenograft model was used to investigate the effects of PVT1 and HK2 on GBC. RESULTS:PVT1 was upregulated in GBC tissues and cells and was positively associated with malignancies and worse overall survival. PVT1 knockdown inhibited cell proliferation, migration, and invasion in vitro and restrained tumor growth in vivo. Further studies demonstrated that PVT1 positively regulated HK2 expression via its competing endogenous RNA (ceRNA) activity on miR-143. Additionally, HK2 expression and function were positively correlated with PVT1. Furthermore, we observed that the PVT1/miR-143/HK2 axis promoted cell proliferation and metastasis by regulating aerobic glucose metabolism in GBC cells. CONCLUSIONS:The results of our study reveal a potential ceRNA regulatory pathway in which PVT1 modulates HK2 expression by competitively binding to endogenous miR-143 in GBC cells, which may provide new insights into novel molecular therapeutic targets for GBC.

BACKGROUND:Intrahepatic cholangiocarcinoma (ICC) is the second most frequent primary liver cancer. The involvement of Y-box binding protein 1 (YBX1) in tumor advancement is well-documented. However, its function in ICC is not fully understood. This study aimed to explore the function and regulatory mechanism of YBX1 in ICC and provide evidence for YBX1 as a potential new approach for immunotherapy in ICC. METHODS:Tissue immunohistochemistry, TCGA, and GEO databases were used to analyze the expression of YBX1 in ICC. The expression of YBX1 was silenced and overexpressed in cell lines. Both in vitro and in vivo assays were conducted to examine the antitumor T-cell responses. Actinomycin D, RNA immunoprecipitation, and methylated RNA immunoprecipitation assays were used to identify mechanism of YBX1 on downstream genes. Immunofluorescence assay was used to validate the association between YBX1 and relevant genes in clinical specimens of ICC. RESULTS:The research findings indicated that ICC exhibited high levels of YBX1 expression, which was strongly associated with unfavorable outcomes. YBX1 promoted tumor progression by suppressing antitumor T-cell responses. YBX1 enhanced signal transducer and activator of transcription 1 (STAT1) translation by serving as a 5-methylated cytosine (m5C) reader and activating the STAT1/PD-L1 pathway. Mouse experiments and clinical samples of ICC confirmed the strong correlation between the levels of YBX1, STAT1, and PD-L1 expression. CONCLUSIONS:YBX1 regulates STAT1 stability in an m5C dependent manner and maintains PD-L1 expression in ICC.

Corona Virus Disease (COVID-19) has become a global public health crisis, and the Omicron variant has rapidly taken over as soon as it was detected Serum circulating metabolites can provide extensive insights into the pathogenesis and diagnosis of many diseases. We included 336 omicron variant cases (OC), 216 recovered cases (RC), and 380 healthy controls (HC) for untargeted metabolomics analysis and analyzed their serum metabolic profiles by liquid chromatography-tandem mass spectrometry. Principal component analysis, orthogonal partial least squares discriminant analysis, t-test analysis and false discovery rate were used to characterize the serum metabolites of OC and RC. In addition, a noninvasive diagnostic model for OC was developed using Receiver operating characteristic analysis. Finally, a correlation analysis was performed using data from our published articles. The results showed that compared with HC, five metabolites, including DL-stachydrine, D-(+)-pipecolinic acid, furazolidone, L-arginine and 5α-dihydrotestosterone glucuronide were significantly elevated and one metabolite, prenylcysteine, was significantly decreased in the serum of OC, and that the increase in L-arginine and the decrease in prenylcysteine led to impaired urea cycling and a high risk of developing atherosclerosis, respectively. These metabolites were not fully restored to healthy human levels in recovered cases. In addition, we constructed a noninvasive diagnostic model for distinguishing Omicron variant patients from healthy individuals based on the six differential metabolites, and achieved high diagnostic efficacy in both the discovery and validation cohorts. Finally, the results of the correlation analysis showed a strong correlation between the alterations in the oropharyngeal microbiome and serum metabolome and the clinical indicators in the omicron variant cases. This study was the first to characterize serum metabolites in OC and RC based on a large clinical cohort, and successfully constructed and validated a noninvasive diagnostic model for Omicron variant patients.

The COVID-19 pandemic,caused by SARS-CoV-2,has dispro-portionately affected elderly populations,especially those with comorbidities such as malignancies.Previous data indicated that individuals over 60 years account for＞80％ of COVID-19-related deaths,largely due to age-related immune senescence,chronic inflammation,and impaired antiviral responses1-3.

Abstract Azvudine is recommended as a priority treatment for patients with Coronavirus Disease 2019 (COVID‐19) during Omicron wave in China, but its efficacy and safety in elderly patients is unknown. In this multicenter, retrospective study, we identified 19763 elderly patients (aged over 60 years) with COVID‐19 from nine hospitals in Henan Province, China. The primary outcome is all‐cause death and the secondary outcome is composite disease progression. After propensity score matching, 4109 Azvudine recipients and 4109 matched controls is included, with average age of 75.15 years. Kaplan–Meier analysis reveales a notably survival and progression‐free benefit in Azvudine treatment. The Cox analysis shows that compared with controls, Azvudine recipients have a 33% lower risk of all‐cause death (95% confidence Interval (CI): 0.580–0.772, p < 0.001), but have no significant difference in composite disease progression (hazard ratio: 0.93, 95% CI: 0.833‐1.046, p = 0.234). Subgroup analysis suggested Azvudine have a stronger protective effect in patients concomitant with antibiotics. Three sensitive analyses confirm the robustness of the findings. The safety of Azvudine in elderly patients is acceptable. These findings indicate that Azvudine therapy can reduce the rate of all‐cause death in hospitalized elderly patients with COVID‐19, and without obvious adverse events.

BackgroundRNA 5-methylcytosine (m5C) plays an important role in the progression of hepatocellular carcinoma (HCC). Dysregulation of ferroptosis is closely associated with HCC. However, the effect of the epigenetic mRNA m5C modification on ferroptosis in HCC remains unclear.MethodsIn this study, ferroptosis was evaluated by detecting lipid reactive oxygen species (lipid ROS), ferrous ion and 4-hydroxynonenal (4-HNE) in xenograft mouse model, diethylnitrosamine (DEN)-initiated HCC model and so forth. The regulatory mechanisms of YBX1 in mRNA translation were elucidated using RNA sequencing, ribosome sequencing, RNA immunoprecipitation (RIP)-sequencing, bisulphite sequencing and immunoprecipitation (IP)-mass spectrometry assays. Dual-luciferase reporter, RIP-qPCR, Co-IP, RNA pulldown and methylated RNA immunoprecipitation (MeRIP)-quantitative polymerase chain reaction (qPCR) assays were performed to validate the mechanism of YBX1 in regulating mRNA translation by m5C modification.ResultsHere, we found that YBX1 promoted the translation of Ring Finger Protein 115 (RNF115) mRNA through m5C modification, thereby inhibiting ferroptosis and promoting HCC development. Moreover, RNF115 was identified as an E3 ubiquitin ligase for dihydroorotate dehydrogenase (DHODH), promoting Lys27 (K27) ubiquitination and inhibiting its autophagic degradation to counteract ferroptosis. In addition, YBX1 bound to the m5C modification sites of RNF115 3 '-untranslated region (UTR) and interacted with Eukaryotic Translation Initiation Factor 4A1 (EIF4A1) to bridge the 5 '-UTR regions, promoting mRNA circularisation and translation, while NOP2/Sun RNA methyltransferase 2 (NSUN2) was identified as responsible for m5C modification of RNF115 mRNA in HCC.ConclusionsThe current work revealed that YBX1 promoted RNF115 mRNA translation in an m5C-dependent manner, thereby regulating DHODH ubiquitination and expression to suppress ferroptosis. This research sheds light on the mechanism of YBX1 in m5C-modified mRNAs translation and ferroptosis, highlighting its promise as a biomarker for prognosis and a target for therapy in HCC.Key points YBX1 inhibits ferroptosis in HCC by regulating the RNF115-DHODH axis. RNF115, an E3 ligase, mediates K27 ubiquitination and autophagic degradation of DHODH. YBX1 binds to the m5C sites of RNF115 mRNA 3 '-UTR and interacts with EIF4A1 to bridge the 5 '-UTR, promoting mRNA circularisation and translation. High expression of YBX1/RNF115 predicts the poor overall survival in HCC.

Herpes simplex virus type 1 (HSV-1) is a prevalent pathogen that can lead to severe diseases, including herpes labialis, keratitis, and encephalitis. The development of novel antiviral therapies is significant due to the limited number of available treatments and the emergence of drug-resistant strains. In this study, a series of aza-fused heterocyclic derivatives were synthesized and evaluated for antiviral efficacy. Compound 5i demonstrated notable antiviral activity in vitro with an EC50 (Effective Concentration 50 %) of 1.95 ± 0.07 μM. This effect was achieved by inhibiting viral replication and targeting viral ICP4 and gD proteins. In addition, the expression of STING and NF-κB signaling pathways was down-regulated, cytokine storm was reduced, and the multi-targeted activity of compound 5i inhibited apoptosis. The high efficacy of compound 5i was demonstrated in a mouse herpes encephalitis model. Infected mice's survival significantly improved, and viral load in brain tissue was substantially reduced in the presence of compound 5i. Furthermore, compound 5i demonstrated favorable safety in preliminary in vivo evaluations, with no adverse effects on major organs observed. In conclusion, the aza-fused heterocyclic derivative 5i has substantial potential as a therapeutic agent for HSV-1 infection, providing a valuable foundation for further drug development and clinical translation.

5-methylcytosine (m5C) is a prevalent posttranscriptional RNA modification that participates in the initiation and progression of various cancers. NSUN2 is the primary RNA methyltransferase responsible for catalyzing the formation of m5C. However, its regulatory role and potential mechanism in osteosarcoma are still unclear. Here, we demonstrated that the NSUN2 expression was markedly upregulated in osteosarcoma tissues and cell lines. Clinically, increased NSUN2 expression was associated with poor prognosis. Functional studies revealed that NSUN2 significantly promoted metastasis and epithelial-mesenchymal transition (EMT) in osteosarcoma. Mechanistically, integrated analysis based on RNA sequencing and expression correlation identified UBE2S as a downstream target gene of NSUN2, while NSUN2 enhanced the stabilization of UBE2S mRNA in an m5C-dependent manner. More importantly, UBE2S overexpression reversed the inhibition of cell invasion and EMT induced by NSUN2 knockdown. Moreover, UBE2S interacted with and ubiquitinated β-catenin, enhancing its stability and activation. Interestingly, osteosarcoma patients with dual-high expression of NSUN2 and UBE2S exhibited shorter overall survival. In summary, our study revealed that NSUN2 facilitated metastasis by enhancing the UBE2S/β-catenin axis, suggesting a potential therapeutic approach for osteosarcoma.

579 Background: Novel treatment options for unresectable HCC are needed. Iparomlimab and tuvonralimab are anti-PD-1 and anti-CTLA-4 antibodies, respectively. The DUBHE-H-106 study aims to assess safety and efficacy of first-line QL1706 or QL1604 + BEV for HCC. Preliminary data have been reported on 2023 ASCO Annual Meeting. Here, we report updated results. Methods: This study consists of three cohorts. Systemic therapy-naive adult patients (pts) with HCC, ≥ one measurable untreated lesion per RECIST v1.1, BCLC stage B–C, Child-Pugh score ≤ 7, not amenable to or progression after locoregional therapy, ECOG performance status of 0–1 were eligible. In Cohort A, six pts received QL1706 5 mg/kg + BEV 15 mg/kg Q3W. If ≤ two pts had dose-limiting toxicities (DLT), another six pts would be enrolled. If ≤ three of twelve pts had DLT, the safe dose of BEV would be determined, and eight more pts would be enrolled. Otherwise, enrollment of another dose group (QL1706 5 mg/kg + BEV 7.5 mg/kg Q3W) would initiate, using the same procedure. If number of DLT exceeded the criteria, further dose reduction of BEV or study termination would be discussed. Then 40–60 pts were randomized 1:1 to Cohort A or B. In Cohort B, pts received QL1604 200 mg + BEV (safe dose) Q3W. Enrollment of Cohort C would initiate according to the preliminary results of Cohort A and B. Pts received QL1706 7.5 mg/kg + BEV (safe dose) Q3W, using the same procedure in Cohort A. If ≤ three of twelve pts had DLT, 8–28 more pts would be enrolled. Results: Between Jun 2021 and Dec 2023, Cohort A, B, and C included 50, 26, and 40 pts, respectively. Baseline data were balanced in each cohort. All pts were in the safety set. No DLT was reported. Incidences of adverse events (AE) were similar in three cohorts. Efficacy evaluable set included 47, 26, and 37 pts in three cohorts. Numerically, QL1706 + BEV showed better efficacy compared to QL1604 + BEV, and higher response and 12-month progression-free survival (PFS) rates were found in Cohort C vs Cohort A. Detailed results were shown in Table. Conclusions: First-line QL1706 or QL1604 + BEV showed acceptable toxicities and promising efficacy for unresectable HCC. QL1706 7.5 mg/kg + BEV 15 mg/kg Q3W may have better anti-tumor activity and were recommended for trials in future. Clinical trial information: NCT05603039 . Endpoints Cohort A Cohort B Cohort C Treatment-related AE (TRAE) 43 (86%) 25 (96%) 37 (92%) Grade ≥ 3 TRAE 24 (48%) 14 (54%) 16 (40%) Serious TRAE 11 (22%) 9 (35%) 10 (25%) Immune-related AE 27 (54%) 9 (35%) 22 (55%) TRAE leading to dose interruption 23 (46%) 16 (62%) 16 (40%) Objective response, n (%; 95% CI) 18 (38%; 25%–54%) 6 (23%; 9%–44%) 16 (43%; 27%–61%) Disease control, n (%; 95% CI) 35 (74%; 60%–86%) 18 (69%; 48%–86%) 30 (81%; 65%–92%) Median PFS (95% CI), months 7.0 (3.1–9.6) 5.4 (2.4–11.0) 7.0 (4.2–not evaluable) 12-month PFS rate (95% CI) 26.8 (14.7–40.4) 24.4 (9.9–42.1) 40.9 (24.3–56.9)

Metastasis accounts for 90% of cancer-related deaths among the patients. The transformation of epithelial cells into mesenchymal cells with molecular alterations can occur during epithelial–mesenchymal transition (EMT). The EMT mechanism accelerates the cancer metastasis and drug resistance ability in human cancers. Among the different regulators of EMT, Wnt/β-catenin axis has been emerged as a versatile modulator. Wnt is in active form in physiological condition due to the function of GSK-3β that destructs β-catenin, while ligand–receptor interaction impairs GSK-3β function to increase β-catenin stability and promote its nuclear transfer. Regarding the oncogenic function of Wnt/β-catenin, its upregulation occurs in human cancers and it can accelerate EMT-mediated metastasis and drug resistance. The stimulation of Wnt by binding Wnt ligands into Frizzled receptors can enhance β-catenin accumulation in cytoplasm that stimulates EMT and related genes upon nuclear translocation. Wnt/β-catenin/EMT axis has been implicated in augmenting metastasis of both solid and hematological tumors. The Wnt/EMT-mediated cancer metastasis promotes the malignant behavior of tumor cells, causing therapy resistance. The Wnt/β-catenin/EMT axis can be modulated by upstream mediators in which non-coding RNAs are main regulators. Moreover, pharmacological intervention, mainly using phytochemicals, suppresses Wnt/EMT axis in metastasis suppression. Graphical abstract

Background SARS-CoV-2 infections usually cause immune dysregulation in the human body. Studies of immunological changes resulting from coinfections with Mycobacterium tuberculosis ( Mtb ) or HIV are limited. Methods We conducted a retrospective study focusing on patients with COVID-19. A total of 550 patients infected with SARS-CoV-2 were enrolled in our study and categorized into four groups based on the presence of coinfections; 166 Delta-infected patients, among whom 103 patients had no coinfections, 52 who were coinfected with Mtb , 11 who were coinfected with HIV, and 384 Omicron-infected patients. By collecting data on epidemiologic information, laboratory findings, treatments, and clinical outcomes, we analyzed and compared clinical and immunological characteristics. Results Compared with those in the Delta group, the median white blood cell, CD4 + T-cell and B-cell counts were lower in the Mtb group and the HIV group. Except for those in the Omicron group, more than half of the patients in the three groups had abnormal chest CT findings. Among the three groups, there were no significant differences in any of the cytokines. Compared with those in the Delta group, the disease duration and LOS were longer in the Mtb group and the HIV group. For unvaccinated Delta-infected patients, in the Mtb and HIV groups, the number of B cells and CD4 + T cells was lower than that in the Delta group, with no significant difference in the LOS or disease duration. In the Mtb group, three (6%) patients presented with a disease duration greater than four months and had decreased lymphocyte and IL17A counts, possibly due to double infections in the lungs caused by SARS-CoV-2 and M. tuberculosis. Conclusions We found that SARS-CoV-2 patients coinfected with Mtb or HIV exhibited a longer disease duration and longer LOS, with a decrease in B cells and CD4 + T cells, suggesting that these cells are related to immune function. Changes in cytokine levels suggest that coinfection with Mtb or HIV does not result in dysregulation of the immune response. Importantly, we discovered a chronic course of coinfection involving more than four months of Mtb and SARS-CoV-2 infection.

5- methylcytosine (m5C) is a prevalent posttranscriptional RNA modification which participates in the initiation and progression of various cancers. NSUN2 is the main RNA methyltransferase import for catalyzing the m5C formation. However, its regulatory role and potential mechanism in osteosarcoma remain unclear. Here, we demonstrated that the NSUN2 expression was markedly upregulated in osteosarcoma tissues and cell lines. Clinically, increased NSUN2 expression was associated with poor prognosis. Functional studies revealed that NSUN2 significantly promoted metastasis and epithelial-mesenchymal transition (EMT) in osteosarcoma. Mechanistically, integrated analysis based on RNA sequencing and expression correlation analysis identified UBE2S as a target downstream gene of NSUN2, while NSUN2 enhanced UBE2S mRNA stabilization in an m5C-dependent manner. More importantly, UBE2S overexpression reversed the inhibition of cell invasion and EMT induced by NSUN2 knockdown. Moreover, UBE2S interacted with and ubiquitinated β-catenin, enhancing its stability and activation. Interestingly, osteosarcoma patients with dual-high expression of NSUN2 and UBE2S exhibited shorter overall survival. In summary, our study revealed that NSUN2 facilitated metastasis by enhancing the UBE2S/β-catenin axis, suggesting a potential therapeutic approach for osteosarcoma.

The modification and recognition of 5-methylcytosine (m5C) are involved in the initiation and progression of various tumor types. However, the precise role and potential mechanism of Y-box-binding protein 1 (YBX1) in esophageal squamous cell carcinoma (ESCC) remains unclear. Here, it is found that YBX1 is frequently upregulated in ESCC compared with matched nontumor tissues. Gain- and loss-of-function assays show that YBX1 promoted the proliferation and metastasis of ESCC cells both in vitro and in vivo. Functional studies revealed that NOP2/Sun RNA methyltransferase family member 2 (NSUN2) is a critical RNA methyltransferase that facilitates YBX1-mediated ESCC progression. Mechanistically, integrated analysis based on RNA immunoprecipitation sequencing (RIP-seq) and m5C methylated RNA immunoprecipitation and sequencing (MeRIP-seq) assays identified spermine oxidase (SMOX) as a target gene containing an m5C site in its coding sequence (CDS) region, which coincided well with the binding site of YBX1. Overexpression of SMOX-WT but not SMOX-Mut partially restored the proliferation and invasion ability of ESCC cells curbed by YBX1 knockdown. Moreover, YBX1 activated the mTORC1 signaling pathway by stabilizing SMOX mRNA. The study reveals that YBX1 promotes ESCC development by stabilizing SMOX mRNA in an m5C-dependent manner, thus providing a valuable therapeutic target for ESCC.