Glioma represents a significant challenge in neuro-oncology due to its highly invasive nature and poor prognosis. Recent studies indicate that ferroptosis, a form of regulated cell death, plays a crucial role in the pathogenesis of glioma. Modulating ferroptosis may offer a novel therapeutic approach for glioma treatment. This study aims to identify ferroptosis-related biomarkers and patterns of immune infiltration in glioma using bioinformatics techniques, and to predict potential therapeutic drugs targeting these biomarkers. Gene expression profiles (GSE16011, GSE50161) were retrieved from the GEO database, while ferroptosis-related genes were sourced from the FerrDb database. Intersection genes were identified using the CytoHubba algorithm and a consensus clustering method. Immune infiltration was assessed using the CIBERSORT algorithm. Functional enrichment analysis and gene set enrichment analysis were conducted with Gene Ontology and Kyoto Encyclopedia of Genes and Genomes databases. Drug targeting predictions were made based on identified hub genes. We identified 10 hub genes: TP53, RRM2, EZH2, CDKN1A, MYCN, KIF20A, BLM, GLS2, HMOX1, and GOT1. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses revealed that ferroptosis is primarily associated with apoptosis, reactive oxygen metabolism, the p53 signaling pathway, and immune regulation. Immune infiltration analysis showed significant differences in the expression of plasma cells, CD8 T cells, follicular helper T cells, activated NK cells, and macrophages between groups. qRT-PCR validation in glioma cell lines confirmed the differential expression of key ferroptosis-related genes, supporting the robustness of our bioinformatic findings. Furthermore, molecular docking demonstrates excellent binding properties between the drug components and key targets, and these key targets were further validated by PCR analysis in vitro. In summary, this study highlights the potential of ferroptosis-related biomarkers in glioma and suggests novel drug targets, providing a foundation for future therapeutic strategies.

This study investigated the molecular mechanisms underlying the anticancer effects of Hedyotis Diffusae Herba (HDH) against esophageal squamous cell carcinoma (ESCC) through network pharmacology and molecular docking approaches. We identified active compounds in HDH using the traditional Chinese medicine systems pharmacology database and analysis platform, while ESCC-related targets were retrieved from the GeneCards database. Drug-disease target interactions were analyzed and visualized through Venn diagrams and network topology analysis. We employed Kyoto encyclopedia of genes and genomes pathway enrichment analysis to elucidate potential therapeutic mechanisms and constructed comprehensive "drug-active ingredient-key target-signaling pathway-disease" networks using Cytoscape software. Key active ingredients and targets were prioritized based on network topological parameters, and their binding interactions were validated through molecular docking using AutoDock software. Our analysis identified 15 bioactive compounds in HDH, including quercetin, beta-sitosterol, and stigmasterol, as primary contributors to its anti-ESCC activity, corresponding to 91 potential therapeutic targets. From the GeneCards database, we identified 6262 ESCC-associated genes, including key oncogenes such as TP53, MET, and EGFR. Notably, 43 genes overlapped between HDH targets and ESCC-related genes, including critical cancer drivers such as EGFR, ERBB2, and MYC. Kyoto encyclopedia of genes and genomes pathway enrichment analysis revealed that HDH's anti-ESCC targets are predominantly involved in the MAPK signaling pathway, p53 signaling pathway, and chemical carcinogenesis-receptor interaction pathways. Molecular docking simulations indicated strong binding affinity and conformational stability between key active compounds (quercetin and beta-sitosterol) and critical target proteins (BCL2 and PRKCA). This study infers the molecular mechanisms through which HDH components may regulate ESCC via an integrated multi-omics approach; however, its computational nature primarily necessitates experimental validation.

The leptin receptor (LEPR) serves as a central regulator of energy balance and metabolic homeostasis, with growing interest in its pleiotropic roles in cancer. However, existing evidence on its oncogenic function remains ambiguous, with studies reporting both tumor-promoting and tumor-suppressive effects across different contexts. This duality complicates the interpretation of LEPR's precise role in carcinogenesis. Moreover, conventional observational studies are inherently limited by residual confounding and reverse causality, leaving the causal relationship between LEPR signaling and site-specific cancer risk unresolved. To address this, we performed a drug-target Mendelian randomization analysis to assess the causal effect of genetically proxied LEPR activity on 16 such cancers. We selected cis-expression quantitative trait loci (cis-eQTLs) associated with LEPR expression in blood from the eQTLGen Consortium (n = 31,684) as instrumental variables, and harmonized them with summary-level genome-wide association study data for cancers from the FinnGen R12 release. Among the 16 evaluated malignancies, our primary finding demonstrated that genetically elevated LEPR signaling was significantly associated with a lower risk of pancreatic cancer (odds ratio = 0.91; 95% CI: 0.87-0.96; P = 3.93 × 10-4). This association withstood Bonferroni correction and was consistent across sensitivity analyses. Suggestive inverse associations were also observed for lung squamous cell carcinoma, gastric cancer, and breast cancer subtypes (P <.05), whereas no significant causal links were detected for the remaining ten cancers. No significant heterogeneity or horizontal pleiotropy was detected. In summary, this drug-target Mendelian randomization study provides concise genetic evidence supporting a protective role of LEPR signaling specifically in pancreatic cancer, with suggestive effects in several other malignancies. These findings inform the pathophysiological understanding of leptin in cancer and highlight the relevance of LEPR-modulating strategies for safety assessment in oncology. Limitations include the use of blood-derived eQTLs and restriction to European ancestry, which may affect generalizability.

This study aimed to retrospectively analyze the clinical characteristics, tumor staging, surgical outcomes, and prognosis of children with MEN2B who presented with MTC. By summarizing our single-center experience, we emphasize the importance of early recognition and genetic screening to provide clinical insights for improving prognosis. Clinical data of six pediatric patients diagnosed with MEN2B in BCH, between January 2019 and December 2023, were reviewed. Demographic characteristics, clinical presentation, laboratory and imaging findings, genetic testing, surgical details, and follow-up information were analyzed. Descriptive statistical methods were used for data analysis. The cohort included 6 patients (2 males, 4 females) with a median age of 9.2 years (range 8.1-14.4 years). All patients harbored the de novo p.M918T RET mutation. All patients exhibited the classic MEN2B phenotype (marfanoid habitus, ocular signs, multiple oral mucosal neuromas, vocal cord nodules, high-arched palate, etc.) accompanied by alacrima and gastrointestinal symptoms. All underwent total thyroidectomy and bilateral central compartment neck dissection, with five undergoing concurrent lateral neck dissection due to suspected metastasis. Postoperative pathology confirmed MTC in all cases, with cervical lymph node metastases present in 4 patients (66.7%). Preoperative calcitonin levels were markedly elevated. After a median postoperative follow-up of 2.8 years (range 2.1 to 4.5 years), only one patient (T2N0M0) achieved biochemical remission.

Actin filament-associated protein 1 antisense RNA 1 (AFAP1-AS1) has been found to be closely associated with the initiation and progression of various tumors; however, its role in oral squamous cell carcinoma (OSCC) remains unclear. AFAP1-AS1 expression in OSCC cells was detected using qRT-PCR. The regulatory effects of AFAP1-AS1 on tumor cell proliferation, migration, and invasive capabilities were systematically evaluated through CCK-8 proliferation, colony formation, wound healing, and Transwell invasion assays. Flow cytometry was employed to quantitatively analyze its impact on cell cycle progression and apoptotic. Based on bioinformatics predictions, a dual-luciferase reporter system was utilized to validate the targeting interactions among AFAP1-AS1, miR-93-3p, and CCND1. Functional rescue experiments were conducted to elucidate the functional regulatory network among them. Furthermore, a xenograft tumor model in nude mice was employed to verify in vivo the promoting effect of AFAP1-AS1 on tumor growth. AFAP1-AS1 was significantly upregulated in OSCC cells. AFAP1-AS1 knockdown inhibited the malignant phenotypes of OSCC cells. Mechanistic studies revealed that AFAP1-AS1 could target miR-93-3p and regulate CCND1 expression, thereby influencing OSCC progression. Subcutaneous tumor model in mice further confirmed the in vivo relevance of the AFAP1-AS1/miR-93-3p/CCND1 axis. AFAP1-AS1 downregulation inhibited OSCC progression through the miR-93-3p/CCND1 axis.

ZNRF3 and RNF43 are closely related transmembrane E3 ubiquitin ligases with significant roles in development and cancer. Conventionally, their biological functions have been associated with regulating WNT signaling receptor ubiquitination and degradation. However, our proteogenomic studies have revealed EGFR as the protein most negatively correlated with ZNRF3/RNF43 mRNA levels in multiple human cancers. Through biochemical investigations, we demonstrate that ZNRF3/RNF43 interact with EGFR via their extracellular domains, leading to EGFR ubiquitination and subsequent degradation facilitated by the E3 ligase RING domain. Overexpression of ZNRF3 reduces EGFR levels and suppresses cancer cell growth in vitro and in vivo, whereas knockout of ZNRF3/RNF43 stimulates cell growth and tumorigenesis through upregulated EGFR signaling. Together, these data suggest ZNRF3 and RNF43 as novel E3 ubiquitin ligases of EGFR and establish the inactivation of ZNRF3/RNF43 as a driver of increased EGFR signaling, ultimately promoting cancer progression. This discovery establishes a connection between two fundamental signaling pathways, EGFR and WNT, at the level of cytoplasmic membrane receptors, uncovering a novel mechanism underlying the frequent co-activation of EGFR and WNT signaling in development and cancer.

Acute myeloid leukemia (AML) harboring BCR::ABL1 is considered a separate diagnostic entity and is classified as adverse in the risk score of the European LeukemiaNet. However, its prognosis could change with the addition of tyrosine kinase inhibitors (TKI) to chemotherapy.

Breast cancer (BC) is the leading cause of cancer death in women. Bidirectional regulation between BC and gut microbiota (GM) is established, but GM's mechanistic role in BC pathogenesis remains unclear. Public BC/control samples and GM genome-wide association study data underwent Mendelian randomization to identify GM-BC associations and GMRGs. DEGs between BC and controls were analyzed. Candidate genes were derived from intersecting DEGs and GMRGs. Machine learning identified biomarkers, validated by expression analysis. GSEA, immune infiltration, drug screening with molecular docking, and scRNA-seq were performed. Intersecting 3455 DEGs with GMRGs yielded eight candidates; MCM6 and NR3C1 were validated as biomarkers, enriched in DNA replication pathways. Immune infiltration showed 13 differential immune cells, with macrophages notably influencing biomarkers. Etoposide exhibited strong binding to biomarkers via docking. scRNA-seq identified epithelial cells as key, with stage-dependent biomarker expression. This study redefines BC as a microbiome-regulated network, identifying the MCM6/NR3C1 biomarker pair for early diagnosis and microbiome-targeted interventions.

Clear cell renal cell carcinoma (KIRC), the most prevalent pathological renal cell carcinoma (RCC) subtype, makes up approximately 75%-84% of total cases. KIRC is characterized by high heterogeneity, high metastasis rates, and a poor prognosis. Its incidence rate has continued to rise in recent years. We sought to construct new prognostic models to optimize treatment decisions, improve clinical benefits, and explore potential therapeutic targets.

Kidney renal clear cell carcinoma (KIRC) is an aggressive malignancy with limited therapeutic options, highlighting the need for novel biomarkers and therapeutic targets. Although endoplasmic reticulum metallopeptidase 1 (ERMP1) has been implicated in cancer progression, its specific role, clinical significance, and underlying mechanisms in KIRC remain poorly defined.

Cholangiocarcinoma (CCA) is a highly aggressive malignancy. 3-Hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2), a mitochondrial enzyme involved in ketogenesis, has been linked to tumor progression, but its role in CCA remains unclear. HMGCS2 expression in CCA tissues was analyzed using TCGA data and immunoblotting (IB). Functional assays were performed in CCA cell lines (HuCCT-1 and RBE) and an in vivo xenograft model. Metabolomics explored HMGCS2-mediated metabolic changes. SIRT3-HMGCS2 interactions were examined via molecular docking, IF, CO-IP, GST pull-down, and CHX assays, with mutational analysis identifying interaction sites. IHC assessed clinical samples. HMGCS2 was downregulated in CCA. Overexpression inhibited proliferation and invasion, while knockdown promoted these effects, consistent in vitro and in vivo. Metabolomics showed HMGCS2 enhanced ketone body synthesis, and exogenous ketone bodies mimicked its antitumor effects. SIRT3 deacetylated HMGCS2 at K310 (with plasmid mutation assay), and low HMGCS2/SIRT3 expression correlated with poor patient survival. SIRT3-mediated deacetylation of HMGCS2 promotes ketone body synthesis, suppressing CCA progression. HMGCS2 is a potential therapeutic target for CCA.

Background: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths globally. Although the hypoxia-inducible factor 1A (HIF1A) pathway is crucial in HCC progression, its regulatory mechanisms remain unclear as mutations in its primary regulator, von Hippel-Lindau tumor suppressor (VHL), are rare in HCC. We aimed to elucidate the role of proliferation and apoptosis adaptor protein 15 (PEA15), identified through proteomic analysis, as a regulator of the VHL/HIF1A pathway and a therapeutic target in HCC. Methods: Proteomic and genomic analyses of over 1,000 HCC samples were conducted, identifying PEA15 amplification. Functional validation involved in vitro and in vivo assays, including gene knockdown, ectopic expression, and antisense oligonucleotide (ASO) therapy in xenograft models. Protein interactions were assessed using immunoprecipitation and ubiquitination assays. Results: We identified 3 clinically distinct HCC subtypes and found that PEA15 was selectively amplified and highly expressed in the mesenchymal (MES) subtype, which exhibited the poorest prognosis. PEA15 acted as a regulator of the VHL/HIF1A pathway and a key oncogene in HCC. The amplification of PEA15 was significantly associated with the poor survival of HCC patients. Moreover, by interacting with the β-domain of VHL, PEA15 promoted HCC cell proliferation and migration by inhibiting VHL's interaction with the VHL/elongin C (ELOC)/elongin B (ELOB)/cullin 2 (CUL2) E3 ligase complex, destabilizing the complex and consequently activating HIF1A. Importantly, pharmacologically inhibiting PEA15 using PEA15 ASO drugs attenuated tumor burden and restored VHL function in a xenograft mouse model. Conclusions: This study identified PEA15 as a potential oncogene in HCC, regulating the VHL/HIF1A axis and driving tumor progression. Targeting PEA15 using ASOs offers a promising therapeutic strategy for HCC, particularly in the MES subtype. These findings provide a basis for further exploration of PEA15-targeted therapies to improve HCC outcomes.

Human leukocyte antigen E (HLA-E) plays a role in tumor immune escape and is associated with poor prognosis in neuroblastoma (NB). This study aimed to investigate the regulatory effect of suberoylanilide hydroxamic acid (SAHA) on HLA-E expression via the PERK/ATF4/CHOP pathway in NB.

Growing evidence suggests a link between the gut microbiome and papillary thyroid carcinoma (PTC), but the causal relationships and the impact on the tumor immune microenvironment (TME) are poorly understood. This study aimed to elucidate the causal role of specific gut microbes in PTC and uncover the underlying immunological and molecular mechanisms. We employed a multi-stage design, beginning with a two-sample Mendelian randomization (MR) analysis using large-scale GWAS data to infer causality. Findings were then validated in 450 PTC patients from The Cancer Genome Atlas (TCGA) by analyzing correlations between microbial abundance, gene expression, immune cell infiltration, and survival. Finally, the core mechanism was confirmed through extensive in vitro experiments with PTC cell lines. Our MR analysis identified a causal association between a genetically predicted higher abundance of the genus Terrisporobacter and an increased risk of PTC (Odds Ratio [OR] = 2.06, 95% Confidence Interval [CI]: 1.34-3.16). In the TCGA cohort, higher intratumoral signals of Terrisporobacter was significantly correlated with an immunosuppressive TME, characterized by increased infiltration of M2 macrophages (ρ = 0.25, p < 0.001) and decreased CD8+ T cells (ρ = -0.19, p = 0.008). Mechanistically, Terrisporobacter abundance was also strongly associated with the upregulation of the oncogene NTRK1 (ρ = 0.35, p < 0.001), which independently predicted poorer overall survival (Hazard Ratio [HR] = 2.15, p = 0.004). In vitro experiments confirmed that supernatant from Terrisporobacter culture not only upregulated NTRK1 expression and promoted PTC cell proliferation but also enhanced invasion and induced cell de-differentiation. Importantly, pharmacological inhibition of TRK signaling reversed the bacteria-induced aggressive phenotype. Our integrated analysis provides robust, multi-layered evidence for a causal role of Terrisporobacter in promoting PTC progression. We define a novel gut-thyroid axis where Terrisporobacter contributes to PTC development by upregulating the NTRK1 oncogene and shaping a pro-tumorigenic, immunosuppressive microenvironment. These findings reveal a new dimension of host-microbe interaction in thyroid cancer and highlight the TME as a key downstream target of microbial influence.

Colorectal cancer (CRC) ranks among the most prevalent gastrointestinal malignancies with liver metastasis being the primary cause of CRC-related death. Although surgical and chemotherapeutic interventions continue to improve, patients with hepatic metastases frequently experience recurrence and limited treatment benefits. Liver metastasis is driven by tumor heterogeneity and immune evasion. Therefore, defining the cellular composition of CRC liver metastases may help identify new therapeutic targets.

PIK3CA is one of the most frequently mutated genes in cervical cancer (CC). However, its clinical utility is hampered by paradoxical treatment-dependent outcomes, restricting its application in precision oncology. To address this issue, we constructed a high-resolution single-cell transcriptomic atlas of the CC tumor microenvironment. It was found that PIK3CA mutations induce a dichotomous TME, simultaneously associated with marked T-cell inflammation and resistance to adaptive immune responses. Malignant epithelial subsets induce CD8+ T-cell exhaustion through both canonical PD-L1-PD-1 signaling and the non-canonical SPP1-CD44 axis. Additionally, PIK3CA mutations enrich for MMP9+ macrophages that promote tumor angiogenesis through ANGPTL4 signaling. This dual landscape of T-cell exhaustion and active angiogenesis provides a framework for the observed synergy between PD-1 blockade and anti-angiogenic therapies. The findings demonstrate that the presence of PIK3CA mutations is a key predictive biomarker for guiding combination immunotherapy in CC and identify a rational basis for co-targeting distinct immune and vascular resistance pathways.

Tumor heterogeneity is a fundamental driver of therapeutic resistance across solid malignancies, arising from genetic, epigenetic, phenotypic, spatial, temporal, and microenvironmental diversity. In tumors developing at mucosal barrier sites, these heterogeneous features are further shaped by the unique immunological context of mucosal tissues, where immune tolerance, chronic inflammation, and continuous antigen exposure create permissive environments for immune escape and adaptive resistance. Accumulating evidence indicates that myeloid cell plasticity, including functional diversification of granulocytes, macrophages, monocytes, and dendritic cells, represents a critical interface between tumor-intrinsic heterogeneity and mucosal immune regulation. These myeloid populations contribute to spatially organized immunosuppressive niches, altered antigen processing and presentation, and therapy-induced immune remodeling, collectively influencing responses to chemotherapy, targeted therapy, and immunotherapy. Advances in single-cell sequencing, spatial transcriptomics, multiplex imaging, and liquid biopsy technologies, coupled with artificial intelligence-enabled analytics, have enabled high-resolution mapping of heterogeneous tumor immune landscapes and revealed convergent resistance mechanisms driven by clonal selection, phenotypic plasticity, microenvironmental buffering, and myeloid-mediated immune suppression. In this review, we synthesize mechanistic and clinical evidence across major cancer types, including colorectal and lung cancers as archetypal mucosal tumors, along with broader examples from breast cancer, melanoma, and immunotherapy-treated malignancies. We highlight how heterogeneous cellular states and immune niches influence clinical outcomes. Finally, we discuss emerging translational strategies to overcome resistance, including rational combination regimens, epigenetic and metabolic targeting, adaptive therapy, myeloid reprogramming approaches, and real-time biomarker monitoring. These approaches aim to restore effective anti-tumor immunity while accounting for the unique constraints of mucosal barrier tissue.

Primary colon squamous cell carcinoma (SCC) is an extremely rare malignancy and associated with a poor prognosis. This case report describes a patient with deficient mismatch repair/microsatellite instability-high (dMMR/MSI-H) ascending colon SCC, who was treated at our institution. After receiving four cycles of programmed cell death -1 (PD-1) blockade monotherapy, the tumor exhibited significant regression, and pathological complete response (pCR) was achieved following surgical resection. This case demonstrates that Anti-PD-1 therapy can induce clinically meaningful tumor regression even in this rare colon SCC subtype, suggesting a potential treatment strategy for dMMR/MSI-H colon SCC. These findings may provide valuable insights for clinicians managing similar cases. However, the feasibility and safety of immunotherapy in dMMR/MSI-H primary colon SCC require further validation through additional clinical studies.

Vorinostat (suberoylanilide hydroxamic acid, SAHA) is a histone deacetylase (HDAC) class I/II inhibitor that has been evaluated in clinical trials for efficacy in pediatric cancers. Previous studies demonstrated cellular responses to SAHA in retinoblastoma (RB), a pediatric intraocular cancer. However, its mechanism of action remains incompletely understood. In this report, we demonstrate that SAHA inhibition of cell proliferation and induction of cell death was associated with the downregulation of the FOXM1 oncogene in the MYCN-driven RB1-/RB1-cell lines WERI-RB1 and Y79, of which Y79 exhibits greater metastatic potential. SAHA also deregulated cell cycle genes that are targeted by FOXM1. Additionally, SAHA inhibited RB metastatic signaling, including inhibiting the expression of MMP2, a transcriptional target of FOXM1. Further, because SAHA inhibition of FOXM1 positively correlated with suppression of the MYCN oncogene, we demonstrated that genomic knockdown of MYCN in the RB cell lines resulted in FOXM1 downregulation. Finally, we showed that FOXM1 inhibition downregulated NF-κβ and inhibition of FOXM1 suppressed FOXM1 expression in the RB cell lines. Taken together, these results indicated that SAHA inhibition of FOXM1 oncogenic signaling may be mediated by MYCN in RB. Although the current data provide a preclinical rationale for the consideration of SAHA either as a single agent or in combination with other therapies, for the treatment of metastatic RB with MYCN-amplified RB1-/RB1-molecular phenotype, further research is warranted to gain greater insight into FOXM1-MYCN interaction in response to SAHA, in this molecular subtype of RB.

The hepatitis B virus X protein (HBx) is a central oncogenic driver in hepatocellular carcinoma (HCC). Although glypican-3 (GPC3) is a phosphatidylinositol proteoglycan-specific biomarker for HCC. However, the combined role of HBx and GPC3 in mediating HCC cell evasion from macrophage phagocytosis remains unclear. Here, we demonstrate that HBx modulates macrophage phagocytosis by regulating GPC3 membrane morphology. Analysis of tissues from 30 patients with hepatocellular carcinoma revealed concomitant upregulation of HBx and GPC3 in tumour specimens. Mechanistically, HBx alters ERK site phosphorylation, thereby influencing the enzymatic activity of Furin protease-which cleaves GPC3-and consequently orchestrating morphological changes of membrane-associated GPC3. To functionally validate this, THP-1 cells were polarized to M1 macrophages and co-cultured with HCC cells. Notably, HBx directly impaired macrophage phagocytosis of HCC cells, an effect mediated through GPC3 morphological dynamics. Collectively, these findings indicate that HBx suppresses macrophage phagocytosis of HCC cells by remodelling membrane-associated GPC3.