Cell Commun Signal. 2026 Sep 11;24(1):488. doi: 10.1186/s12964-026-03206-2.

ABSTRACT

BACKGROUND: While over 170 RNA modifications have been identified and implicated in various cancers, their role in hepatocellular carcinoma (HCC) progression is increasingly recognized. Despite this established relevance in tumor biology, the landscape of RNA modifications in the peripheral blood of HCC patients-and their potential diagnostic utility-remains largely unexplored.

METHODS: Peripheral blood samples from patients with HCC, liver cirrhosis (LC), and normal healthy (NH) controls were collected. The abundances of 55 RNA modifications were quantified using liquid chromatography-tandem mass spectrometry (LC-MS/MS) to assess their diagnostic potential for HCC, particularly at early stages. Correlations among these modifications and their associations with clinical parameters were analyzed. Simultaneously, differentially expressed genes, including those encoding RNA-modifying enzymes, were screened in peripheral blood. The biological relevance of the identified signatures was subsequently validated using in vitro co-culture and in vivo syngeneic HCC mouse models.

RESULTS: Compared to the combined non-HCC group (NH and LC), the abundances of 11 RNA modifications were significantly altered in both overall and stage I HCC groups, with N²,N²-dimethylguanosine (m^2,2G) emerging as a key component exhibiting the most pronounced dysregulation. A diagnostic model centered on an m^2,2G-based modification panel achieved area under the curves (AUCs) of 0.901 and 0.891 for detecting HCC and stage I HCC, respectively, demonstrating promising diagnostic potential. Notably, the incorporation of two upregulated genes in peripheral blood-IFI27 and CCR2-significantly enhanced the model's performance, yielding improved AUCs of 0.972 and 0.968, respectively. Further analysis revealed distinct correlation patterns among RNA modifications, as well as between RNA modifications and clinical laboratory parameters, exhibiting both shared and HCC-specific features that suggest systemic reprogramming of RNA modification network in HCC. This biological relevance was confirmed by elevated m^2,2G abundances in human lymphocytes co-cultured with HCC cells and blood from a syngeneic HCC mouse model.

CONCLUSIONS: This study systematically profiled peripheral blood RNA modifications and provided preliminary evidence supporting their potential as diagnostic biomarkers for HCC. By integrating key modifications (m^2,2G, m^2,2,7G, m^6,6A) with two mRNA markers (IFI27 and CCR2), we developed a multi-omics signature that demonstrated promising diagnostic performance, particularly for early-stage HCC.

PMID:42732057 | PMC:PMC13570552 | DOI:10.1186/s12964-026-03206-2

Cancer Commun (Lond). 2026 Sep 11;46:0048. doi: 10.34133/cancomm.0048. eCollection 2026.

ABSTRACT

Background: Cancer cells frequently acquire adaptive resistance to targeted therapies; however, strategies capable of concurrently overcoming treatment tolerance and reactivating cell death pathways are currently lacking. Here, we investigated the dual role of ferredoxin 1 (FDX1) in modulating both multikinase inhibitor (MKI) sensitivity and cuproptosis susceptibility in hepatocellular carcinoma (HCC), and sought to develop a therapeutic approach for reversing resistance. Methods: HCC models, both in vitro and in vivo, were employed to investigate the role of FDX1 in MKI resistance and cuproptosis evasion. Polysome profiling, SunTag translation reporters, CRISPR-Cas9 mutagenesis, and mass spectrometry were employed to delineate the underlying mechanisms. A codelivery nanoliposome system was engineered and tested in orthotopic HCC models. Results: Prolonged exposure to MKIs led to the down-regulation of FDX1 protein levels, resulting in MKI resistance and cuproptosis tolerance in HCC both in vitro and in vivo. Mechanistically, we found that MKIs inactivated protein kinase B (PKB, also known as AKT)-mechanistic target of rapamycin (mTOR) signaling, thereby suppressing the SET and MYND domain-containing protein 2 (SMYD2)-mediated methylation of YTH domain family protein 1 (YTHDF1) at lysine 515 (K515). Hypomethylated YTHDF1 was degraded via next to BRCA1 gene 1 protein (NBR1)-dependent autophagy, leading to the repression of N6-methyladenosine modification-dependent translation of FDX1 mRNA. FDX1 deficiency drove MKI resistance by reactivating AKT survival signaling while impairing cuproptosis through reduced divalent copper ions (Cu²⁺) to monovalent copper ions (Cu⁺) conversion and the loss of protein lipoylation. Additionally, restoring FDX1 expression through NBR1 knockdown or YTHDF1 overexpression overcame MKI resistance and resensitized HCC cells to cuproptosis. Finally, a nanoliposomal system, super cuproptosis detonator liposome, designed for the codelivery of NBR1 small interfering RNA, a copper ionophore, and sorafenib restored FDX1-dependent cuproptosis and exhibited marked anti-HCC efficacy, suppressing HCC growth in vivo. Conclusions: MKIs suppressed SMYD2-mediated YTHDF1 methylation at K515 via the inactivation of AKT-mTOR signaling. This led to the inhibition of FDX1 translation, resulting in AKT signaling reactivation and protein lipoylation impairment, effects that contributed to both MKI resistance and cuproptosis tolerance in HCC. Overcoming MKI resistance and resensitizing cells to cuproptosis by targeting NBR1-mediated YTHDF1 degradation using a nanoliposomal codelivery system represents a promising strategy for HCC treatment.

PMID:42729649 | PMC:PMC13562797 | DOI:10.34133/cancomm.0048

Front Pharmacol. 2026 Aug 28;17:1899849. doi: 10.3389/fphar.2026.1899849. eCollection 2026.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease with limited therapeutic options and marked molecular heterogeneity. Despite available antifibrotic therapies, disease progression remains poorly predictable, highlighting the need for improved mechanistic understanding and therapeutic targeting. This review summarizes recent advances in multi-omics research to elucidate the molecular mechanisms underlying IPF and to identify potential biomarkers and pharmacological targets. Multi-omics studies, including genomics, epigenomics, transcriptomics, proteomics, metabolomics, microbiome profiling, and single-cell sequencing, have revealed key pathogenic mechanisms in IPF. Genetic susceptibility factors such as MUC5B promoter variants and telomere-related genes contribute to disease risk. Epigenetic regulation, including DNA methylation, histone modifications, and non-coding RNAs, plays a central role in fibrotic remodeling. Transcriptomic and proteomic analyses have identified dysregulated signaling pathways, including TGF-β, mTOR, cellular senescence, and extracellular matrix remodeling. Metabolomic alterations indicate disrupted lipid and amino acid metabolism. Importantly, integration of multi-omics datasets enables the identification of molecular endotypes, candidate biomarkers, and potential therapeutic targets. However, challenges including data integration, tissue heterogeneity, limited cohort size, and the need for functional validation remain important barriers to clinical translation. Continued development of multi-omics approaches may facilitate more accurate disease classification and support the development of personalized therapeutic strategies for IPF.

PMID:42729333 | PMC:PMC13561894 | DOI:10.3389/fphar.2026.1899849

Cell Commun Signal. 2026 Sep 11;24(1):488. doi: 10.1186/s12964-026-03206-2.

ABSTRACT

BACKGROUND: While over 170 RNA modifications have been identified and implicated in various cancers, their role in hepatocellular carcinoma (HCC) progression is increasingly recognized. Despite this established relevance in tumor biology, the landscape of RNA modifications in the peripheral blood of HCC patients-and their potential diagnostic utility-remains largely unexplored.

METHODS: Peripheral blood samples from patients with HCC, liver cirrhosis (LC), and normal healthy (NH) controls were collected. The abundances of 55 RNA modifications were quantified using liquid chromatography-tandem mass spectrometry (LC-MS/MS) to assess their diagnostic potential for HCC, particularly at early stages. Correlations among these modifications and their associations with clinical parameters were analyzed. Simultaneously, differentially expressed genes, including those encoding RNA-modifying enzymes, were screened in peripheral blood. The biological relevance of the identified signatures was subsequently validated using in vitro co-culture and in vivo syngeneic HCC mouse models.

RESULTS: Compared to the combined non-HCC group (NH and LC), the abundances of 11 RNA modifications were significantly altered in both overall and stage I HCC groups, with N²,N²-dimethylguanosine (m^2,2G) emerging as a key component exhibiting the most pronounced dysregulation. A diagnostic model centered on an m^2,2G-based modification panel achieved area under the curves (AUCs) of 0.901 and 0.891 for detecting HCC and stage I HCC, respectively, demonstrating promising diagnostic potential. Notably, the incorporation of two upregulated genes in peripheral blood-IFI27 and CCR2-significantly enhanced the model's performance, yielding improved AUCs of 0.972 and 0.968, respectively. Further analysis revealed distinct correlation patterns among RNA modifications, as well as between RNA modifications and clinical laboratory parameters, exhibiting both shared and HCC-specific features that suggest systemic reprogramming of RNA modification network in HCC. This biological relevance was confirmed by elevated m^2,2G abundances in human lymphocytes co-cultured with HCC cells and blood from a syngeneic HCC mouse model.

CONCLUSIONS: This study systematically profiled peripheral blood RNA modifications and provided preliminary evidence supporting their potential as diagnostic biomarkers for HCC. By integrating key modifications (m^2,2G, m^2,2,7G, m^6,6A) with two mRNA markers (IFI27 and CCR2), we developed a multi-omics signature that demonstrated promising diagnostic performance, particularly for early-stage HCC.

PMID:42732057 | PMC:PMC13570552 | DOI:10.1186/s12964-026-03206-2

Clin Exp Med. 2026 Jul 26;26(1):329. doi: 10.1007/s10238-026-02264-7.

ABSTRACT

KANSL2, a core component of the NSL histone acetyltransferase complex, has been implicated in tumorigenesis. However, its pan-cancer relevance and functional role in liver hepatocellular carcinoma (LIHC) remain unclear. Multi-omics data from TCGA, GEO, and HPA were integrated to systematically evaluate KANSL2 expression, clinical significance, genomic alterations, and immune associations across cancers. Functional enrichment, immune infiltration analyses, and single-cell transcriptomics were performed. In vitro assays were conducted to validate the biological effects of KANSL2 in LIHC cells. KANSL2 is broadly upregulated across cancers and exhibits strong diagnostic performance. Elevated KANSL2 expression correlates with unfavorable prognosis, particularly in LIHC. Mechanistically, KANSL2 and its co-expressed genes are enriched in cell-cycle progression. KANSL2 expression is also closely associated with immune infiltration and immunoregulatory signaling within the tumor microenvironment, with single-cell data indicating preferential expression in proliferative T-cell subsets. Functional experiments demonstrate that KANSL2 silencing suppresses proliferation, migration, and invasion, and induces G2/M phase arrest in LIHC cells. Notably, its effects on apoptosis are limited, suggesting that KANSL2 primarily drives tumor progression through cell-cycle-dependent mechanisms. This study identifies KANSL2 as a key regulator of tumor progression and immune remodeling in LIHC. By promoting malignancy predominantly via cell-cycle control, KANSL2 represents a promising biomarker for diagnosis and prognosis, and a potential therapeutic target.

PMID:42726304 | PMC:PMC13569553 | DOI:10.1007/s10238-026-02264-7

Clin Exp Med. 2026 Jul 26;26(1):329. doi: 10.1007/s10238-026-02264-7.

ABSTRACT

KANSL2, a core component of the NSL histone acetyltransferase complex, has been implicated in tumorigenesis. However, its pan-cancer relevance and functional role in liver hepatocellular carcinoma (LIHC) remain unclear. Multi-omics data from TCGA, GEO, and HPA were integrated to systematically evaluate KANSL2 expression, clinical significance, genomic alterations, and immune associations across cancers. Functional enrichment, immune infiltration analyses, and single-cell transcriptomics were performed. In vitro assays were conducted to validate the biological effects of KANSL2 in LIHC cells. KANSL2 is broadly upregulated across cancers and exhibits strong diagnostic performance. Elevated KANSL2 expression correlates with unfavorable prognosis, particularly in LIHC. Mechanistically, KANSL2 and its co-expressed genes are enriched in cell-cycle progression. KANSL2 expression is also closely associated with immune infiltration and immunoregulatory signaling within the tumor microenvironment, with single-cell data indicating preferential expression in proliferative T-cell subsets. Functional experiments demonstrate that KANSL2 silencing suppresses proliferation, migration, and invasion, and induces G2/M phase arrest in LIHC cells. Notably, its effects on apoptosis are limited, suggesting that KANSL2 primarily drives tumor progression through cell-cycle-dependent mechanisms. This study identifies KANSL2 as a key regulator of tumor progression and immune remodeling in LIHC. By promoting malignancy predominantly via cell-cycle control, KANSL2 represents a promising biomarker for diagnosis and prognosis, and a potential therapeutic target.

PMID:42726304 | PMC:PMC13569553 | DOI:10.1007/s10238-026-02264-7

Front Immunol. 2026 Aug 27;17:1812306. doi: 10.3389/fimmu.2026.1812306. eCollection 2026.

ABSTRACT

Stroke-associated pneumonia (SAP) is the most common infectious complication following acute stroke. The limited efficacy of conventional antimicrobial therapy suggests that SAP may be fundamentally a syndrome driven by dysregulated cross-system interactions. This review proposes the "gut microbiota-immune axis" (GMIA) as a comprehensive framework for the development of SAP and systematically discusses the potential mechanisms by which post-stroke microbial-derived metabolic signals-including short-chain fatty acids (SCFAs), bile acids, tryptophan metabolites, and endotoxins-drive systemic immune reprogramming, predisposing patients to SAP. Based on the GMIA, we highlight several promising intervention strategies, including dietary modulation, precision antibiotic use, probiotics, fecal microbiota transplantation (FMT), supplementation with microbial metabolites, and receptor-targeted therapies, and summarize the current clinical translation related to the GMIA. Future research directions require high-quality clinical trials that integrate multi-omics data from the microbiome with immune biomarkers and clinical parameters. Such an approach is essential for constructing validated risk stratification models and advancing the management of SAP from empirical anti-infective treatment toward a precision medicine model centered on GMIA-based immune modulation.

PMID:42724580 | PMC:PMC13560329 | DOI:10.3389/fimmu.2026.1812306

J Thorac Dis. 2026 Aug 31;18(8):950. doi: 10.21037/jtd-2026-1704. Epub 2026 Aug 28.

ABSTRACT

BACKGROUND AND OBJECTIVE: Traditionally, two primary systems have been employed for staging small cell lung cancer (SCLC): the Veterans Administration Lung Study Group (VALG) system and the International Association for the Study of Lung Cancer (IASLC) tumor, node, metastasis (TNM) system. The term "limited disease" is defined differently: VALG characterizes it as disease encompassed within a single tolerable radiation field, while IASLC defines it as the lack of distant metastases (M0). Patients with N3 disease frequently satisfy VALG extensive-stage (ES) criteria while meeting IASLC limited-stage (LS) criteria, resulting in a notable staging discrepancy. Therefore, this review aims to clarify the clinical challenges posed by this staging overlap and provide insights for standardizing staging terminology and optimizing therapeutic decision-making in N3 SCLC.

METHODS: A narrative review utilizing a systematized search strategy was conducted. While strict adherence to PRISMA guidelines was not pursued because the extensive heterogeneity of the literature precluded a formal meta-analysis, rigorous search criteria were applied to minimize selection bias. Databases including PubMed, Web of Science, Embase, the Cochrane Library, and China National Knowledge Infrastructure (CNKI) were searched for literature from January 2000 to March 2026. Studies examining stage N3 SCLC, spatial metastatic burden, and definitional inconsistencies between the VALG and IASLC staging systems were analyzed to assess their effects on treatment dosimetry, systemic therapy, and survival outcomes.

KEY CONTENT AND FINDINGS: The staging overlap in N3 SCLC leads to heterogeneous clinical management depending on its spatial metastatic burden, and this highly variable cohort can be stratified into distinct prognostic subgroups based on the anatomical distribution (single-region vs. multi-region) of the involved lymph nodes.

CONCLUSIONS: These findings should guide clinical trial design and terminology. Clinical decision-making must transcend historical paradigms and technical constraints. Future strategies must incorporate spatial evaluations of metastatic burden alongside innovative multimodal tools, such as artificial intelligence (AI) and multi-omics, to facilitate tailored therapy for SCLC.

PMID:42724560 | PMC:PMC13559235 | DOI:10.21037/jtd-2026-1704

Front Endocrinol (Lausanne). 2026 Aug 27;17:1782791. doi: 10.3389/fendo.2026.1782791. eCollection 2026.

ABSTRACT

Neuroendocrine neoplasms (NENs) are biologically heterogeneous tumors in which differentiation/grade and hormonal functionality are intersecting but non-equivalent axes. This review focuses on functional and non-functional well-differentiated neuroendocrine tumors (NETs), principally gastroenteropancreatic and pancreatic NETs, and critically evaluates how site, lineage, stage, tumor burden, genomic and epigenetic alterations, immune-stromal remodeling, metabolic adaptation, microbiome-associated signals, and treatment pressure converge on metastasis and recurrence. Apparent outcome differences by functionality are inconsistent after clinicopathological adjustment: non-functional presentation is often enriched for delayed diagnosis and adverse features, whereas functional subtypes range from typically indolent insulinomas to clinically aggressive hormone-producing tumors. We reconcile these observations through a layered model in which lineage-defining alterations and chromatin/telomere programs establish cellular state; signaling and metabolic plasticity enable stress adaptation; and hypoxia, angiogenesis, immune cells, fibroblasts, extracellular matrix, and therapy create selective niches for dissemination and relapse. We also define computational strategies for heterogeneous multi-omics integration and a staged biomarker-validation pathway. Evidence remains dominated by pancreatic NETs, and causal support is weakest for microbiome-functionality relationships and several proposed cross-omic links. A spectrum-based framework is therefore most useful when it generates testable, site- and grade-specific hypotheses rather than treating functionality as an isolated prognostic variable.

PMID:42724134 | PMC:PMC13559159 | DOI:10.3389/fendo.2026.1782791