Prostate cancer is a worldwide leading malignancy, and the exploration of initiation mechanisms and therapeutic targets remains an important challenge. In this study, transcriptomic and clinical data from wide-used prostate cancer cohorts were integrated to establish a novel prognostic model and explore the biological significance of its core genes. Differential expression analysis combined with LASSO-Cox regression identified a three-gene prognostic model consisting of MECR, HVCN1, and NGFR. This model could independently predict patient outcomes and demonstrated superior predictive performance compared with conventional clinicopathological variables. Among these genes, MECR was the only one associated with poor prognosis. Functional studies revealed that MECR could promote proliferation, migration, and reduce apoptosis-related nuclear morphological changes in prostate cancer cell. Mechanistically, MECR could regulate PI3K/AKT pathway activity and immune-related cell mechanisms. In immunocompetent syngeneic tumor models, MECR knockdown significantly inhibited tumor progression and was associated with increased CD8+ T-cell activation. We found that CD8+ T-cell depletion could partially rescue the antitumor effects of MECR silencing, indicating that CD8+ T-cell-mediated immunity contributes to the antitumor effects of MECR silencing. Collectively, our findings identify MECR as a potential regulator linking tumor progression, apoptosis-related cellular phenotype, and immune microenvironment remodeling in prostate cancer. By integrating tumor-intrinsic and immune-associated mechanisms, our results provide new insights into molecular pathways in prostate cancer development and immune evasion related therapeutic resistance.

BackgroundProstate cancer (PCa) is frequently associated with poor prognosis, and immunotherapy has shown limited efficacy. This study aimed to identify novel necroptosis-related long non-coding RNAs (lncRNAs) that could predict patient outcomes and guide personalized treatment.MethodsTranscriptomic data from The Cancer Genome Atlas (TCGA) were analyzed using co-expression analysis and univariate Cox regression to identify lncRNAs associated with PCa progression. A necroptosis-related lncRNA prognostic model was constructed using Least Absolute Shrinkage and Selection Operator (LASSO) and validated via Kaplan-Meier survival analysis, time-dependent receiver operating characteristic (ROC) curves, Cox regression, and calibration plots. Functional analyses included Gene set enrichment analysis (GSEA), principal component analysis (PCA), immune profiling, and half-maximal inhibitory concentration (IC50) predictions to explore therapeutic implications.ResultsWe established a nine-lncRNA necroptosis-related signature with strong prognostic performance. Among these, NR2F1-AS1 was identified as a core oncogenic lncRNA, showing marked upregulation in PCa tissues and promoting proliferation, invasion, and migration in vitro. The two inferred risk groups demonstrated distinct immune characteristics: hot tumors (Cluster 2) exhibited higher infiltration of activated immune cells, increased immune checkpoint expression, and greater predicted sensitivity to immunotherapy, whereas cold tumors showed immunosuppressive infiltration patterns and lower checkpoint levels. These features allowed the model to robustly distinguish cold from hot tumor phenotypes.ConclusionNecroptosis-related lncRNAs, particularly NR2F1-AS1, may serve as prognostic biomarkers and inform immune-based stratification, supporting more precise personalized treatment strategies for PCa.

BACKGROUND:Although circRNAs are increasingly implicated in tumor biology, most studies emphasize expression changes while overlooking subcellular distribution. The mechanisms governing circRNA nuclear export in bladder cancer (BCa) and their contribution to progression are poorly defined. METHODS:Differential expressed circRNAs between BCa and adjacent tissues were identified through bioinformatic analysis. Oncologic phenotypes were assessed using CCK-8, colony-formation, transwell, EdU assays in vitro, and subcutaneous xenograft and tail-vein lung metastasis mouse models in vivo. The circSTX6 interactome and transcript-level effects were characterized by RNA-seq, RNA immunoprecipitation (RIP), RNA pull-down, and mass spectrometry. Hypoxia treatment, nuclear-cytoplasmic fractionation, and FISH were used to quantify circSTX6 subcellular localization and oxygen-dependent dynamics. RESULTS:circSTX6 was upregulated in BCa tissues and cells and promoted malignant phenotypes both in vitro and in vivo. Hypoxia increased circSTX6 nuclear retention. Mechanistically, hypoxia induced KCMF1-mediated ubiquitination and degradation of URH49 while upregulating ALYREF, thereby impairing URH49-dependent circSTX6 nuclear export and further promoting circSTX6 nuclear retention. Nuclear-retained circSTX6 bound HNRNPA2B1 and stabilized IGF1 mRNA, activating a circSTX6/HNRNPA2B1/IGF1 axis that enhanced BCa proliferation and migration. CONCLUSION:Hypoxia remodels circSTX6 nuclear export through URH49 degradation and ALYREF upregulation, resulting in circSTX6 nuclear retention and enhanced IGF1-mediated BCa progression.

BACKGROUND: The cardiac voltage-gated sodium channel Nav1.5, encoded by SCN5A, plays a critical role in cardiac electrophysiology. SCN5A variants represent a series of frequently identified genetic findings in molecular autopsies, with established associations across multiple arrhythmia syndromes including long QT syndrome type 3, Brugada syndrome, progressive cardiac conduction disease, sinus node dysfunction, atrial fibrillation, atrial standstill, and dilated cardiomyopathy. Recently, an increasing number of familial cases with early-onset sick sinus syndrome (SSS) were reported, bringing more challenges in forensic genetic diagnosis. METHODS: We investigated a four-generation family with SSS, characterized by a history of pacemaker implantation and sudden cardiac death (SCD). Genetic analyses were performed to identify the underlying pathogenic variant, and electrophysiological properties were evaluated using patch-clamp recordings. RESULTS: We identified a rare SCN5A missense variant, NM_198056.3(SCN5A,rs199473620): c.4720G>A (p.E1574K), in this family. Subsequent analyses demonstrated that the mutated site is highly conserved in the voltage-gated sodium channel family, as well as across species. Electrophysiological experiments showed that this mutation significantly attenuated the function of Nav1.5 channel, potentially revealing the pathogenic mechanism of SCN5A c.4720G>A variant. CONCLUSIONS: Our study identified a rare SCN5A missense variant and classified it as likely pathogenic following the ACMG framework, thereby expanding the phenotypic spectrum of SCN5A-associated SSS and providing a potential forensic diagnostic molecular target for unexplained deaths with negative morphological alterations.

Reprogramming of glucose metabolism is a hallmark of cancer that not only fuels tumor growth but also profoundly regulates cell fate by modulating susceptibility to metal-dependent cell death. This review systematically delineates the mechanistic landscape through which tumor glucose metabolic reprogramming governs ferroptosis and cuproptosis, two emerging forms of regulated cell death driven by iron and copper, respectively. We highlight that glucose metabolism functions as a shared upstream hub, wherein distinct metabolic branches-including glycolysis, the pentose phosphate pathway, the hexosamine biosynthesis pathway, and lactate metabolism-differentially sculpt cellular vulnerability to these death modalities. In ferroptosis, these pathways converge on the NADPH-GSH-GPX4 axis to reinforce antioxidant capacity and lipid remodeling, thereby elevating the ferroptotic threshold. Conversely, cuproptosis sensitivity is dictated by mitochondrial oxidative metabolism and the availability of lipoylated TCA cycle proteins, both of which are suppressed under glycolysis-dominant states. We further discuss how tumor microenvironmental factors, particularly acidification, modulate cuproptosis execution and therapeutic response. Finally, we review emerging therapeutic strategies that leverage metabolic intervention, nanoplatform-based delivery, and combination therapies to exploit these vulnerabilities. By framing glucose metabolism as a central metabolic shunt that regulates the balance between ferroptosis and cuproptosis, this review provides a unified framework for understanding metal-dependent cell death in cancer and offers a roadmap for developing metabolism-targeted combination therapies.

Background:Pyroptosis is an inflammatory form of programmed cell death that may remodel the tumor immune microenvironment and influence clinical outcomes. However, the prognostic value of pyroptosis-related molecular patterns and their translational implications in bladder cancer remain incompletely defined. This study aimed to identify pyroptosis-related molecular subtypes, develop and externally validate a subtype-derived prognostic signature, and explore its associations with immune and therapeutic features in bladder cancer. Methods:The Cancer Genome Atlas-bladder cancer cohort (TCGA-BLCA) was used as the development cohort, GSE13507 and GSE31684 as external validation cohorts, and IMvigor210 as an exploratory immunotherapy-treated cohort. Pyroptosis-related molecular subtypes were identified by non-negative matrix factorization (NMF), and pathway activity and immune infiltration were assessed by gene set variation analysis (GSVA) and single-sample gene set enrichment analysis (ssGSEA). A subtype-derived six-gene prognostic signature was developed using least absolute shrinkage and selection operator Cox (LASSO-Cox) regression, and performance was evaluated by Kaplan-Meier analysis, time-dependent receiver operating characteristic (ROC) curves, and calibration. Results:Two pyroptosis-related molecular subtypes (C1/C2) with distinct survival and immune characteristics were identified. A subtype-derived six-gene prognostic signature comprising ECM1, FER1L4, FKBP10, ANXA1, ARL4C, and CTSE stratified patients into high- and low-risk groups in the development and validation cohorts and remained significantly associated with overall survival (OS) after multivariable adjustment in the TCGA-BLCA cohort. Higher risk scores were associated with higher pathological grade and advanced T stage. Risk stratification was also associated with mutational profiles, immune checkpoint expression, and immunophenoscore (IPS) differences, while CellMiner analysis generated exploratory drug-sensitivity clues. Conclusions:We established pyroptosis-related molecular subtypes and developed a subtype-derived six-gene prognostic signature that was evaluated across multiple independent cohorts. The model is associated with immune microenvironment features and genomic context, and offers translational clues for immunotherapy and targeted strategies, warranting further prospective and experimental validation.

Inducing cuproptosis for cancer therapy currently relies on supraphysiological copper or copper ionophores. Although serum copper is elevated in patients with prostate cancer, whether this is sufficient to trigger physiological cuproptosis remains unclear. Here, we show that tumor copper levels positively correlate with androgen receptor (AR) activity, and castration-resistant prostate cancer (CRPC) with hyperactivated AR exhibits pathological copper accumulation. AR activation enhances copper uptake while simultaneously conferring tolerance to copper toxicity, creating a buffered copper state. This adaptive response is mediated by metal-responsive transcription factor 1 (MTF1), which is transcriptionally upregulated by AR and undergoes EP300-dependent lactylation of lysine 218, promoting copper-induced nuclear translocation. Nuclear MTF1 activates metallothioneins (MT1E, MT1F, and MT1M) that sequester cytosolic copper and restrict mitochondrial copper accumulation. Disrupting MTF1 collapses this buffering system, enabling endogenous copper to trigger cuproptosis and suppress CRPC growth. These findings identify cuproptosis as a therapeutically exploitable vulnerability in CRPC.

Naïve T cells maintain a delicate balance between quiescence and rapid activation, which involves multiple layers of regulation beyond transcription. Here, we identify the RNA modification N6,2'-O-dimethyladenosine (m6Am) and its methyltransferase PCIF1 as critical enforcers of T cell quiescence. During CD4+ T cell activation, m6Am levels are dynamically downregulated. T-cell-specific PCIF1 knockout (cKO) mice exhibit potent tumor suppression, driven by enhanced Th1 differentiation and subsequent amplification of NK cell cytotoxicity. Mechanistically, PCIF1 represses STAT1 translation via m6Am modification of its mRNA, thereby constraining Th1 commitment. Activation-induced PCIF1 downregulation releases this translational brake, enabling rapid Th1 polarization. Crucially, we identify Suramin as a pharmacological PCIF1 inhibitor that disrupts m6Am modification, boosts Th1 responses, and suppresses tumor growth. Our findings establish the PCIF1-m6Am-STAT1 axis as a translational checkpoint governing T cell differentiation and suggest that targeting PCIF1 represents a potential strategy for tumor immunotherapy.

Prostate cancer (PC) is a highly prevalent malignancy in men with substantial prognostic heterogeneity. The present study aimed to identify novel prognostic biomarkers and investigate their functional roles and underlying mechanisms in PC. To this end, integrated bioinformatics analyses were performed using The Cancer Genome Atlas‑prostate adenocarcinoma cohort and two Gene Expression Omnibus datasets. A total of 95 common differentially expressed genes were identified and were significantly enriched in the STAT3 signaling pathway. Lasso and Cox regression analyses screened nine independent prognostic genes, among which SRRT exhibited the highest risk coefficient. The constructed risk model showed strong predictive performance for disease‑free survival and favorable calibration in nomogram analysis. Experimental validation demonstrated that SRRT was markedly upregulated in PC tissues and cell lines, and functional assays revealed that SRRT knockdown inhibited, whereas overexpression promoted, proliferation and migration of DU145 and PC‑3 cells in vitro and tumor growth in vivo. Mechanistically, SRRT enhanced STAT3 phosphorylation, and activation of STAT3 by colivelin partially reversed the suppressive effects of SRRT silencing, indicating that SRRT promotes PC progression through activation of the STAT3 signaling pathway. Collectively, SRRT acts as an independent adverse prognostic biomarker that promotes PC progression, and the present findings provide integrated bioinformatic and experimental evidence linking SRRT to STAT3 pathway activation.

To develop a deep learning (DL) model based on MRI to predict muscle-invasive bladder cancer (MIBC). A total of 559 patients, including 521 patients in our center and 38 patients in external centers were collected from 2012 to 2023 to construct the DL model. In this study, the DL model was utilized to differentiate between MIBC and NMIBC based on three-channel image inputs, including original T2WI images, segmented bladder, and regions of interest. Inception V3 was employed for model construction. The accuracy, sensitivity (SN), specificity (SP), positive predictive value (PPV) and negative predictive value (NPV) for predicting MIBC by DL model were 92.4%, 94.7%, 91.5%, 81.8% and 97.7% in the validation set and 92.1%, 86.8%, 94.6%, 88.5% and 93.8% in the internal test set. In the external test set, these values were 81.6%, 57.1%, 87.1%, 50.0% and 90.0%. Additionally, the accuracy, SN, SP, PPV, and NPV for predicting MIBC were 93.5%, 100%, 93.4%, 11.1%, and 100% in VI-RADS 2; 80.0%, 66.7%, 87.2%, 73.7% and 82.9% in VI-RADS 3; 90.3%, 91.7%, 85.7%, 95.7%, 75.0% in VI-RADS 4. The accuracy, SN, and PPV were 93.9%, 93.9%, and 100% in VI-RADS 5. The DL model based on T2WI can effectively predict MIBC and serve as a valuable complement to VI-RADS 3.

Bladder cancer, as a highly heterogeneous malignant tumor of the urinary system, is significantly affected by tumor metabolic reprogramming in its response to immunotherapy. This review systematically elaborates on the molecular mechanisms of abnormal glucose and lipid metabolism in the bladder cancer microenvironment and immune escape, and discusses precision treatment strategies based on metabolic regulation. In the future, it will be necessary to combine spatiotemporal omics and artificial intelligence technologies to construct a multi-target intervention system for the metabolic–immune interaction network, promoting a paradigm shift in precision treatment for bladder cancer.

Metabolic reprogramming, characterized by hyperactive glycolysis, is a hallmark of bladder cancer (BCa) progression. Here, we identify lactate dehydrogenase A (LDHA) as a central metabolic node coupling glycolytic flux to epigenetic regulation of the immune checkpoint molecule PD-L1. Transcriptomic and survival analyses reveal that dysregulated glycolytic enzymes, particularly LDHA, correlate with poor prognosis and immunotherapy response in BCa patients. Mechanistically, LDHA-driven lactate production induces histone H4K5 lactylation (H4K5la), facilitated by the acetyltransferase EP300, which directly activates PD-L1 transcription. Depletion of LDHA or EP300 reduces H4K5la levels and suppresses PD-L1 expression. Critically, EP300 knockdown reverses PD-L1 upregulation induced by LDHA overexpression, establishing a causal LDHA-EP300-H4K5la-PD-L1 axis that drives immune evasion. Furthermore, RNA immunoprecipitation and luciferase reporter assays suggest that m6A RNA modification may potentiate LDHA overexpression. Collectively, this work unveils a dual-layered mechanism-metabolic lactate flux and histone lactylation that orchestrates immune evasion in BCa, proposing LDHA and EP300 as actionable targets to restore antitumor immunity.

Exploring the impact of professional identity on the academic performance of students is crucial for improving teaching effectiveness and educational outcomes in this field. Forensic medicine is a niche interdisciplinary discipline in the medical system. However, current educational literature on professional identity development does not adequately address forensic medicine students. This study aimed to assess the professional identity among forensic medicine students, explore factors associated with professional identity, and determine the role of professional identity in shaping students’ learning engagement and their subsequent academic achievements. A cross-sectional study was executed for forensic medicine students from a medical university in Jiangsu Province, East China between November and December 2023. Using the method of cluster sampling, 159 undergraduates majoring in forensic medicine were investigated. Data were collected using the demographic questionnaire, and the scales of professional identity, learning engagement, and academic achievement. Linear regression was used to explore professional identity-associated factors. Pearson correlation and mediation analysis were used to analyze the relationship between professional identity, learning engagement, and academic achievement. The mean score of professional identity was 3.85. Grade (senior: β = 0.353, P = 0.004; fifth-year: β = 0.392, P = 0.001), student leader experience (β = 0.157, P = 0.037), specialty selection (major assignment: β=-0.215, P = 0.014), knowledge of the specialty before enrollment (β = 0.095, P = 0.033), and current knowledge of the specialty (β = 0.245, P = 0.000) were the statistically significant factors influencing professional identity. Professional identity, learning engagement, and academic achievement were positively correlated (P < 0.001). Learning engagement played an intermediate role between professional identity and academic achievement, accounting for 49.445

While mTOR plays a key role in the development of pulmonary arterial hypertension (PAH), its suppressor, AMPKα, acts as an inhibitor. Although mTOR-driven transcriptional upregulation of the plasma membrane exchanger and amino acid transporter xCT, encoded by the Slc7a11 gene, is critical for cell proliferation and tumorigenesis, the involvement of xCT in PAH remains unexplored. In this study, we found that xCT expression was elevated in hypoxia-treated human pulmonary arterial endothelial cells (HPAECs) and the lungs of hypoxia-exposed mice and Sugen5416/hypoxia (SuHx)-induced PAH mice. Knockout of xCT prevented the development of PAH and right heart failure in SuHx-conditioned mice. The xCT inhibitor sulfasalazine prevented and reversed SuHx-induced PAH in mice. Deleting and inhibiting xCT activated AMPKα and inactivated mTOR in mouse lungs with PAH and in HPAECs. Sulfasalazine suppressed mTOR through activation of AMPKα in HPAECs. The mTOR inhibitor rapamycin reduced xCT expression, activated AMPKα, and suppressed mTOR in HPAECs. These findings suggest that xCT promotes the development of PAH, likely through suppression of AMPKα and activation of mTOR. Blockage of xCT and mTOR or activation of AMPKα by existing drugs such as sulfasalazine, sirolimus, and metformin may offer readily therapeutic strategies for PAH.

The limited response rate and substantial interindividual variability in immunotherapy outcomes remain major barriers to improving prognosis in patients with bladder cancer (BCa). As central effectors of antitumor immunity, the extent of CD8 + T cell infiltration into tumors is a key determinant of immunotherapy response. Members of the histone deacetylase (HDAC) family play critical roles in modulating tumor immune evasion and sensitivity to immunotherapy, making HDAC inhibitors of clinical interest. A retrospective analysis was performed using data from the IMvigor210 clinical trial and follow-up data from patients with locally advanced BCa who received adjuvant immunotherapy at our center, assessing the association between HDAC1–11 expression and immunotherapy response. RNA sequencing, gene set enrichment analysis (GSEA), chromatin immunoprecipitation PCR (ChIP-PCR), co-immunoprecipitation (Co-IP), mass spectrometry, lysine site mutagenesis, RNA immunoprecipitation, and bioinformatics analysis were employed to outline the HDAC7–BTRC–SRSF7–CCL5 pathway. The immunoregulatory function of HDAC7 was evaluated using CD8 + T cell co-culture assays and tumor models in humanized NOG (HuNOG) mice. Virtual screening, MicroScale Thermophoresis (MST), and HDAC activity assays were conducted to identify potential HDAC7 specific inhibitor. The immunosensitizing effect of Pinocembrin on BCa immunotherapy was validated using a C57BL/6 mouse tumor-bearing model. Among the HDAC family members, only HDAC7 expression was significantly associated with immunotherapy response. HDAC7 was overexpressed in BCa and correlated with poorer prognosis. Functional assays demonstrated that HDAC7 suppresses CD8 + T cell infiltration, thereby reducing sensitivity to PD-1 antibody treatment. Mechanistically, HDAC7 reduced acetylation at lysine 24 of the splicing regulator SRSF7, enhancing BTRC-mediated ubiquitination and degradation of SRSF7, which promoted the processing and expression of CCL5 mRNA-a chemokine essential for CD8 + T cell recruitment. Furthermore, Pinocembrin was identified as a selective HDAC7 inhibitor that restores CD8 + T cell infiltration and improves immunotherapy efficacy in BCa. HDAC7 represents a promising diagnostic and therapeutic target in BCa immunotherapy. Pinocembrin, as a specific HDAC7 inhibitor, holds potential as a combination therapy agent to improve immunotherapy response in BCa.

Quercetin, a ubiquitous dietary flavonoid, has garnered significant scientific interest for its potential as an ergogenic aid in endurance sports. This interest is predicated on robust preclinical evidence demonstrating its potent antioxidant, anti-inflammatory, and mitochondrial biogenesis-stimulating properties. However, a persistent disconnect remains between promising laboratory findings and the equivocal, inconsistent, and often modest results reported in human trials with athletes. This review critically and systematically evaluates the scientific literature concerning quercetin's purported antioxidant and fatigue-resisting properties in the context of endurance training. We dissect the primary molecular mechanisms through which quercetin is proposed to act, including the activation of the nuclear factor erythroid 2–related factor 2 (Nrf2) antioxidant response pathway, modulation of the peroxisome proliferator–activated receptor-gamma coactivator-1α (PGC-1α)/sirtuin-1 (SIRT1) axis for mitochondrial biogenesis, and inhibition of the nuclear factor kappa-light-chain-enhancer of activated B cells inflammatory signaling cascade. The core of this review is a critical analysis of the human performance and recovery data, juxtaposing studies that show benefit with those that report null effects. We synthesize the key controversies that dominate the field, focusing on the critical confounding roles of poor bioavailability, participant training status, supplementation dosage, and timing. The evidence suggests that quercetin's most reliable effects may lie in accelerating recovery from exercise-induced muscle damage (EIMD) and reducing soreness, rather than directly enhancing maximal endurance performance. Its primary value may be as a “training adaptogen” that modulates cellular stress responses, thereby improving fatigue resistance over time. We conclude that quercetin's poor oral bioavailability is the principal barrier that has likely confounded the majority of human research to date. Future research must prioritize the use of high-bioavailability formulations to definitively ascertain whether the impressive preclinical benefits of quercetin can be translated into meaningful, practical applications for endurance athletes.

The peroxidase (POD)-like nanozymes, particularly those with atomic Fe-Nx sites, have demonstrated exceptional catalytic potential in cancer cell ferroptosis. The biodegradable hemoglobin (Hb) is recognized as an Fe-N5 POD-like nanozyme expected to replace the carbon-based ones, while its uncontrollable catalytic reaction remains a safety concern. Here, inspired by the carbon monoxide (CO) poisoned Hb, we develop a controllable and biodegradable catalytic nanoplatform DPHCO which integrates carboxyhemoglobin (HbCO) and platinum(IV) prodrug into -CH2SSCH2- bridged dendritic mesoporous organosilica nanoparticles (DMON). The Fe-N5 site of HbCO could be temporarily deactivated during the blood circulation. In tumor tissue, the poisoned site will be in situ reactivated by the H2O2-driven valence modulation of heme iron, along with CO desorption. The reactivated Hb performs POD-like activity during the ferric-ferryl redox cycle, adhering to Michaelis-Menten kinetics and density function theory (DFT) calculation results. Both in vitro and in vivo data suggest that the reactivated Hb and released CO could induce lipid peroxidation and cancer cell ferroptosis, which is further boosted by cisplatin synergy. This gas modification and iron valence-driven modulation provide a feasible approach for toggling the "OFF/ON" activity of the catalytic site, which would inspire the development of nanozymes for precision oncotherapy.

Background: The significance of circular RNA in tumour biology is increasingly recognized. This study aims to explore the value of circFAM64A(3) in the proliferation and immune evasion of bladder cancer. Methods: Bioinformatics were used to identify the differentially expressed circular RNAs in bladder cancer. Proliferation assay, co-culture assay and flow cytometry assay confirmed the oncogenic and immune-evading characteristics of circFAM64A(3) in bladder cancer in vitro and in vivo. Further, mRNA sequencing, RNA pulldown, and RNA immunoprecipitation were used to confirm the downstream targets and pathways regulated by circFAM64A(3). CUT&TAG assay confirmed HIF-1 alpha promoted the expression of circFAM64A(3) under hypoxic. Results: CircFAM64A(3) was significantly high expression in bladder cancer tissues and related with poor prognosis of bladder cancer patients. CircFAM64A(3) promoted bladder cancer cells proliferation and immune evasion in vitro and in vivo. Mechanistically, circFAM64A(3) acted as a sponge to miR-149-5p and reduced the binding of miR-149-5p to IL-6 3 '-UTR. Then, IL-6 activated the JAK/STAT pathway and caused an increase of PDL1. Under hypoxic environment, HIF-1 alpha bound to the promoter of FAM64A and promoted circFAM64A(3) transcription. Conclusion: HIF-1 alpha/circFAM64A(3)/miR-149-5p/IL-6 axis was an important regulatory pathway in bladder cancer proliferation and immune evasion. CircFAM64A(3) may serve as a novel and potentially valuable biological target.

This review systematically elucidates lactylation as a novel post-translational modification bridging metabolic dynamics and epigenetic regulation. It orchestrates disease progression and therapy resistance through a tripartite network encompassing metabolic reprogramming, epigenetic remodeling, and immune microenvironment rewiring. Mechanistically, histone lactylation activates oncogenic and immune-suppressive transcriptional programs, whereas non-histone lactylation establishes a multidimensional regulatory axis involving metabolic enzyme activity modulation, signaling cascade activation, and immune landscape remodeling. Emerging evidence reveals lactylation-mediated therapy resistance through enhanced DNA repair, autophagy activation, and immunosuppressive barrier formation. Current limitations include incomplete site-specific analysis, ambiguous enzymatic regulation, and clinical translation challenges. Future directions should prioritize multi-omics approaches for dynamic network analysis and development of precision therapeutic strategies.