Comb Chem High Throughput Screen. 2026 Mar 11. doi: 10.2174/0113862073398293251205055042. Online ahead of print.

ABSTRACT

INTRODUCTION: This study aimed to investigate the protective effects of Siji Kangbingdu Mixture (SKM) against acute lung injury (ALI) in mice and to elucidate its underlying mechanisms.

METHODS: ALI was induced in Kunming mice via intranasal administration of LPS (5 mg/kg), followed by oral SKM treatment for 7 days. Lung wet-to-dry (W/D) ratio, histopathology, multiomics analysis, and network pharmacology were performed. Key targets and pathways were identified through dynamic KEGG analysis and validated by Western blotting.

RESULTS: SKM treatment ameliorated alveolar hemorrhage, alveolar wall disruption, septal thickening, edema, and inflammatory cell infiltration. Integrated multi-omics analysis revealed that SKM primarily modulated the Ras signaling pathway, reducing the protein expression of Phospho- MEK1/2, Raf1, Phospho-ERK1/2, and RASH/RASK/RASN, thereby contributing to the treatment of ALI.

DISCUSSION: SKM alleviated LPS-induced ALI in mice by inhibiting the Ras pathway, highlighting the pathway's role in ALI pathogenesis. However, due to limitations of the animal model and incomplete validation, further studies combining clinical research and in vitro experiments are needed to confirm its efficacy and mechanism.

CONCLUSIONS: SKM shows potential to ameliorate ALI by suppressing inflammatory responses and reducing local tissue fibrosis. The combination of metabolomics, transcriptomics, and network pharmacology elucidated its mechanism, while Western blot analysis suggested that its therapeutic effect is associated with downregulation of the Ras signaling pathway.

PMID:41830142 | DOI:10.2174/0113862073398293251205055042

Cancers (Basel). 2026 Feb 25;18(5):735. doi: 10.3390/cancers18050735.

ABSTRACT

BACKGROUND: Lactate accumulation is increasingly recognized as a feature of tumor metabolic reprogramming that can coincide with immune dysregulation and aggressive phenotypes. The prognostic and immunologic relevance of lactate-associated heterogeneity in lung cancer remains to be clarified.

METHODS: We curated lactate-related genes and identified prognostic candidates in lung cancer cohorts. Consensus clustering was applied to define lactate-associated molecular subtypes, followed by characterization of survival and tumor microenvironment features. A LASSO-based gene signature was developed to generate an individual-level risk score and an integrated nomogram. Multi-omics analyses were used to evaluate concordance between transcriptomic and proteomic alterations. Single-cell transcriptomic data were analyzed to explore cellular heterogeneity in lactate-related programs. In vitro assays evaluated the response of candidate genes to lactate exposure and assessed cell migration and invasion under proliferation-inhibited conditions after genetic perturbation.

RESULTS: Two lactate-associated molecular subtypes were identified with distinct overall survival and divergent immune microenvironment features. Subtype 1 was associated with better outcomes and a more immune-inflamed profile, whereas Subtype 2 was associated with poorer outcomes and a myeloid-enriched, immunosuppressive contexture. Pathway analyses indicated subtype-associated differences in extracellular matrix-related processes and apoptosis-associated signaling. We developed an 11-gene prognostic signature and nomogram that stratified patients by risk across TCGA and GEO cohorts. Multi-omics integration highlighted ANLN, FGA, and DKK1 as consistently dysregulated at both transcript and protein levels. Among these candidates, DKK1 showed lactate-responsive induction in vitro. DKK1 perturbation altered lactate-enhanced migratory and invasive phenotypes and was accompanied by changes in intracellular lactate levels and global protein lactylation, supporting a potential feedforward relationship between lactate exposure, DKK1 expression, and lactylation.

CONCLUSIONS: This study characterizes lactate-associated molecular heterogeneity in lung cancer and provides a lactate-related subtype framework and prognostic risk model for patient stratification. The findings nominate DKK1 as a lactate-responsive candidate linked to migration/invasion phenotypes and lactate/lactylation changes in vitro.

PMID:41827671 | PMC:PMC12985219 | DOI:10.3390/cancers18050735

Cell Commun Signal. 2026 Mar 14. doi: 10.1186/s12964-026-02793-4. Online ahead of print.

NO ABSTRACT

PMID:41826981 | DOI:10.1186/s12964-026-02793-4

Comb Chem High Throughput Screen. 2026 Mar 11. doi: 10.2174/0113862073398293251205055042. Online ahead of print.

ABSTRACT

INTRODUCTION: This study aimed to investigate the protective effects of Siji Kangbingdu Mixture (SKM) against acute lung injury (ALI) in mice and to elucidate its underlying mechanisms.

METHODS: ALI was induced in Kunming mice via intranasal administration of LPS (5 mg/kg), followed by oral SKM treatment for 7 days. Lung wet-to-dry (W/D) ratio, histopathology, multiomics analysis, and network pharmacology were performed. Key targets and pathways were identified through dynamic KEGG analysis and validated by Western blotting.

RESULTS: SKM treatment ameliorated alveolar hemorrhage, alveolar wall disruption, septal thickening, edema, and inflammatory cell infiltration. Integrated multi-omics analysis revealed that SKM primarily modulated the Ras signaling pathway, reducing the protein expression of Phospho- MEK1/2, Raf1, Phospho-ERK1/2, and RASH/RASK/RASN, thereby contributing to the treatment of ALI.

DISCUSSION: SKM alleviated LPS-induced ALI in mice by inhibiting the Ras pathway, highlighting the pathway's role in ALI pathogenesis. However, due to limitations of the animal model and incomplete validation, further studies combining clinical research and in vitro experiments are needed to confirm its efficacy and mechanism.

CONCLUSIONS: SKM shows potential to ameliorate ALI by suppressing inflammatory responses and reducing local tissue fibrosis. The combination of metabolomics, transcriptomics, and network pharmacology elucidated its mechanism, while Western blot analysis suggested that its therapeutic effect is associated with downregulation of the Ras signaling pathway.

PMID:41830142 | DOI:10.2174/0113862073398293251205055042

Cancers (Basel). 2026 Feb 25;18(5):735. doi: 10.3390/cancers18050735.

ABSTRACT

BACKGROUND: Lactate accumulation is increasingly recognized as a feature of tumor metabolic reprogramming that can coincide with immune dysregulation and aggressive phenotypes. The prognostic and immunologic relevance of lactate-associated heterogeneity in lung cancer remains to be clarified.

METHODS: We curated lactate-related genes and identified prognostic candidates in lung cancer cohorts. Consensus clustering was applied to define lactate-associated molecular subtypes, followed by characterization of survival and tumor microenvironment features. A LASSO-based gene signature was developed to generate an individual-level risk score and an integrated nomogram. Multi-omics analyses were used to evaluate concordance between transcriptomic and proteomic alterations. Single-cell transcriptomic data were analyzed to explore cellular heterogeneity in lactate-related programs. In vitro assays evaluated the response of candidate genes to lactate exposure and assessed cell migration and invasion under proliferation-inhibited conditions after genetic perturbation.

RESULTS: Two lactate-associated molecular subtypes were identified with distinct overall survival and divergent immune microenvironment features. Subtype 1 was associated with better outcomes and a more immune-inflamed profile, whereas Subtype 2 was associated with poorer outcomes and a myeloid-enriched, immunosuppressive contexture. Pathway analyses indicated subtype-associated differences in extracellular matrix-related processes and apoptosis-associated signaling. We developed an 11-gene prognostic signature and nomogram that stratified patients by risk across TCGA and GEO cohorts. Multi-omics integration highlighted ANLN, FGA, and DKK1 as consistently dysregulated at both transcript and protein levels. Among these candidates, DKK1 showed lactate-responsive induction in vitro. DKK1 perturbation altered lactate-enhanced migratory and invasive phenotypes and was accompanied by changes in intracellular lactate levels and global protein lactylation, supporting a potential feedforward relationship between lactate exposure, DKK1 expression, and lactylation.

CONCLUSIONS: This study characterizes lactate-associated molecular heterogeneity in lung cancer and provides a lactate-related subtype framework and prognostic risk model for patient stratification. The findings nominate DKK1 as a lactate-responsive candidate linked to migration/invasion phenotypes and lactate/lactylation changes in vitro.

PMID:41827671 | PMC:PMC12985219 | DOI:10.3390/cancers18050735

Am J Surg Pathol. 2026 Jun 1;50(6):695-704. doi: 10.1097/PAS.0000000000002533. Epub 2026 Mar 13.

ABSTRACT

With the application of molecular techniques in pathologic diagnosis, several novel primary pulmonary epithelial tumors have been continuously discovered and classified under the WHO classification of thoracic tumors. Recently, a pulmonary tumor with NFATC2 :: NUTM2B fusion was first documented, but the spectrum of NFATC2::NUTM2 fusion variants and their associated pathologic features remains incompletely characterized. Coincidentally, we also found and described 6 primary pulmonary tumors harboring recurrent NFATC2::NUTM2A/E fusions through integrated genomic analysis. These patients, including 4 females and 2 males, with a median age of 53 years, presented with incidentally detected peripheral lung nodules composed of monotonous epithelioid cells arranged in cords, nests, and trabeculae within a prominent desmoplastic stroma. All tumors exhibited a consistent immunophenotype: CK5/6+/GATA3+/calponin+/EMA+/DOG1 (perinuclear dot-like staining)/p63-. High-throughput chromosome conformation capture (Hi-C) analysis showed the structural variation of NFATC2::NUTM2E in all 6 cases, whereas RNA sequencing detected the fusion transcripts in 5 cases ( NFATC2::NUTM2A , n=2; NFATC2::NUTM2E , n=3). Ultrastructural examination of 1 case suggested epithelial differentiation. All patients remained disease-free after complete resection (median follow-up: 24 mo; range: 9 to 41 mo). These findings define a novel primary pulmonary tumor entity driven by NFATC2::NUTM2 fusions, and characterized by a distinctive immunophenotype, expanding the spectrum of NUTM2 -associated neoplasms. Our study underscores the utility of multiomics approaches for characterizing rare neoplasms and provides a diagnostic framework for this entity.

PMID:41821426 | DOI:10.1097/PAS.0000000000002533

Int J Cancer. 2026 Mar 13. doi: 10.1002/ijc.70419. Online ahead of print.

ABSTRACT

Lung cancer, the leading cause of global cancer-related mortality, is categorized into small-cell and non-small-cell subtypes. The heterogeneous non-small-cell lung cancer group is further subcategorized primarily into adenocarcinoma, squamous cell carcinoma, and large cell carcinoma, each underpinned by distinct molecular alterations. Although traditional serum biomarkers aid in subtype differentiation and treatment monitoring, their utility is limited by challenges such as poor specificity due to inflammatory confounders and the difficulty of dynamically tracking therapeutic resistance. Recent advances have identified emergent subtype-specific biomarkers that reflect metabolic reprogramming, epigenetic dysregulation, stemness signatures, and interactions within the immune microenvironment. By integrating analytes such as ctDNA, exosomal RNAs, and urinary DNA with multi-analyte panels and advanced imaging, liquid biopsies offer a promising avenue to enhance early detection accuracy, prognostication, and dynamic therapy monitoring. Nevertheless, the clinical adoption is hindered by several challenges, including incomplete validation, the need for technical standardization, intratumoral heterogeneity, and inter-ethnic variability. The convergence of artificial intelligence (AI)-enhanced multi-omics with biomarker-guided therapeutics represents a transformative strategy with the potential to overcome resistance, mitigate ethnic disparities, and ultimately transform lung cancer into a chronic, manageable disease. Therefore, prioritizing clinically validated AI-integrated platforms is pivotal to achieve precision oncology.

PMID:41826059 | DOI:10.1002/ijc.70419

Dev Cell. 2026 Mar 12:S1534-5807(26)00079-1. doi: 10.1016/j.devcel.2026.02.014. Online ahead of print.

ABSTRACT

Unexplored biological matter-including uncharacterized genetic elements, molecular entities, and microbial components-remains poorly understood. Here, we use integrated multi-omics approaches to identify and characterize previously unrecognized protein products encoded by circular RNAs (circRNAs) in human tissue specimens and to delineate their roles in the progression of lung adenocarcinoma (LUAD). The transcription of precursor mRNA by RNA polymerase Ⅱ subunit A (RPB1) is crucial for the biogenesis of these potential circRNA-encoded proteins. Functional and translational analyses link their expression to distinct pathological stages of LUAD in patients. The protein RIPK1-98, encoded by circRIPK1, was identified as functionally distinct from its parental gene product, receptor-interacting serine/threonine kinase 1 (RIPK1). RIPK1-98 modulates cyclin-dependent kinase 2 (CDK2)-dependent cell-cycle regulation, thereby facilitating tumor proliferation in cellular and animal models. Together, these findings suggest that RIPK1-98 serves as a biomarker for cell-cycle progression in LUAD and highlight its potential as a therapeutic target to counteract resistance to first-line treatments, such as osimertinib.

PMID:41825439 | DOI:10.1016/j.devcel.2026.02.014

Gastric Cancer. 2026 Mar 13. doi: 10.1007/s10120-026-01718-x. Online ahead of print.

ABSTRACT

BACKGROUND: 5-Fluorouracil (5-FU) remains a cornerstone of first-line chemotherapy for gastric cancer, yet the emergence of resistance severely compromises its clinical efficacy. Although ferroptosis suppression has been recognized as a pivotal mechanism of chemoresistance, the mitochondrial regulatory processes involved remain poorly understood.

METHODS: We integrated clinical specimen analysis, in vitro and in vivo functional assays, multi-omics profiling, and molecular docking to delineate the role of the mitochondrial oxidoreductase OXNAD1 in mediating 5-FU resistance in gastric cancer, and to assess the therapeutic potential of the natural polyphenol resveratrol as a chemosensitizing agent.

RESULTS: OXNAD1 was found to be significantly overexpressed in gastric cancer tissues and cell lines, correlating with unfavorable prognosis and enhanced 5-FU resistance. Mechanistically, OXNAD1 directly bound to and suppressed the ferroptosis driver PTGS2, thereby attenuating lipid peroxidation and mitochondrial damage, ultimately restraining ferroptosis and promoting drug resistance. Notably, resveratrol disrupted the OXNAD1-PTGS2 interaction by directly binding OXNAD1, reinstating ferroptotic activity, markedly enhancing the cytotoxic effect of 5-FU in resistant cells, and potentiating the antitumor efficacy of 5-FU in xenograft models.

CONCLUSION: The OXNAD1-PTGS2 axis constitutes a critical metabolic-cell death cross-regulatory pathway underlying 5-FU resistance in gastric cancer. Targeting this axis with resveratrol provides a promising combinatorial strategy to overcome chemoresistance.

PMID:41824193 | DOI:10.1007/s10120-026-01718-x

Int J Cancer. 2026 Mar 13. doi: 10.1002/ijc.70419. Online ahead of print.

ABSTRACT

Lung cancer, the leading cause of global cancer-related mortality, is categorized into small-cell and non-small-cell subtypes. The heterogeneous non-small-cell lung cancer group is further subcategorized primarily into adenocarcinoma, squamous cell carcinoma, and large cell carcinoma, each underpinned by distinct molecular alterations. Although traditional serum biomarkers aid in subtype differentiation and treatment monitoring, their utility is limited by challenges such as poor specificity due to inflammatory confounders and the difficulty of dynamically tracking therapeutic resistance. Recent advances have identified emergent subtype-specific biomarkers that reflect metabolic reprogramming, epigenetic dysregulation, stemness signatures, and interactions within the immune microenvironment. By integrating analytes such as ctDNA, exosomal RNAs, and urinary DNA with multi-analyte panels and advanced imaging, liquid biopsies offer a promising avenue to enhance early detection accuracy, prognostication, and dynamic therapy monitoring. Nevertheless, the clinical adoption is hindered by several challenges, including incomplete validation, the need for technical standardization, intratumoral heterogeneity, and inter-ethnic variability. The convergence of artificial intelligence (AI)-enhanced multi-omics with biomarker-guided therapeutics represents a transformative strategy with the potential to overcome resistance, mitigate ethnic disparities, and ultimately transform lung cancer into a chronic, manageable disease. Therefore, prioritizing clinically validated AI-integrated platforms is pivotal to achieve precision oncology.

PMID:41826059 | DOI:10.1002/ijc.70419

Dev Cell. 2026 Mar 12:S1534-5807(26)00079-1. doi: 10.1016/j.devcel.2026.02.014. Online ahead of print.

ABSTRACT

Unexplored biological matter-including uncharacterized genetic elements, molecular entities, and microbial components-remains poorly understood. Here, we use integrated multi-omics approaches to identify and characterize previously unrecognized protein products encoded by circular RNAs (circRNAs) in human tissue specimens and to delineate their roles in the progression of lung adenocarcinoma (LUAD). The transcription of precursor mRNA by RNA polymerase Ⅱ subunit A (RPB1) is crucial for the biogenesis of these potential circRNA-encoded proteins. Functional and translational analyses link their expression to distinct pathological stages of LUAD in patients. The protein RIPK1-98, encoded by circRIPK1, was identified as functionally distinct from its parental gene product, receptor-interacting serine/threonine kinase 1 (RIPK1). RIPK1-98 modulates cyclin-dependent kinase 2 (CDK2)-dependent cell-cycle regulation, thereby facilitating tumor proliferation in cellular and animal models. Together, these findings suggest that RIPK1-98 serves as a biomarker for cell-cycle progression in LUAD and highlight its potential as a therapeutic target to counteract resistance to first-line treatments, such as osimertinib.

PMID:41825439 | DOI:10.1016/j.devcel.2026.02.014

Mol Cell Biochem. 2026 Mar 13. doi: 10.1007/s11010-026-05510-4. Online ahead of print.

ABSTRACT

Pulmonary fibrosis (PF), a progressive interstitial lung disease with elusive pathogenesis, remains a therapeutic challenge. Emerging evidence suggests cuproptosis-a copper-dependent cell death pathway-may play a regulatory role in disease progression. This study aims to elucidate cuproptosis's biological function and establish a prognostic model for PF. Through integrative analysis of single-cell RNA-seq data from bleomycin (BLM)-induced mouse models and bulk RNA-seq data from idiopathic pulmonary fibrosis (IPF) patients, we identified cuproptosis-related genes (CRGs) using LASSO regression and Cox regression. A novel 4-CRG signature (LIAS, LIPT1, ATP7A, PDHB) was constructed to stratify patients into distinct risk groups in the GSE70866 cohort, where high-risk individuals exhibited poorer survival and enhanced extracellular matrix/lipid metabolism activity via GO/KEGG analysis. Experimental validation in BLM-induced mouse models, TGF-β1-stimulated fibroblast-to-myofibroblast transition assays, and human IPF specimens demonstrated significant downregulation of CRGs through qRT-PCR and immunohistochemical analyses. Functional assays revealed impaired cell viability and elevated cuproptosis markers in fibrotic microenvironments. Our findings establish an inverse correlation between cuproptosis and PF progression, and propose a robust risk-score model for clinical prognosis prediction. This multi-omics approach provides new insights into copper-mediated regulatory mechanisms in fibrogenesis.

PMID:41824199 | DOI:10.1007/s11010-026-05510-4

Front Oncol. 2026 Feb 25;16:1743620. doi: 10.3389/fonc.2026.1743620. eCollection 2026.

ABSTRACT

Lung cancer remains the leading cause of cancer-related mortality, yet current precision oncology approaches remain overwhelmingly tumor-centric, guided by genomic alterations and immune biomarkers, while largely neglecting the profound impact of aging biology on treatment response. While emerging evidence suggests that aging biology can modify therapeutic benefit and toxicity, its clinical integration remains uneven and largely investigational. In this review, we explicitly distinguish the chronological aging from biological aging to clarify how host biology modifies therapeutic benefit and toxicity. We synthesize mechanistic, translational, and early clinical evidence, while explicitly noting areas where prospective validation is lacking, to reframe personalization of lung cancer therapy through an age-conscious lens. We summarize data indicating that immunosenescence is associated with T-cell exhaustion, myeloid dominance, and extracellular matrix stiffening, features that may contribute to immune-evasive tumor phenotypes and attenuated responses to immune checkpoint blockade in subsets of patients, while pediatric cases, though rare, illustrate how global precision initiatives like iTHER and ZERO enable cautious adaptation of adult therapies. Moving beyond chronological age, we discuss biological age biomarkers, including PhenoAgeAccel, epigenetic clocks, telomere length, and frailty indices, which outperform traditional metrics in predicting risk, resistance, and toxicity, and propose integrating these tools into trial design, screening, and care planning which show promise for risk stratification and toxicity prediction but are not yet validated for routine treatment selection. Looking forward, we outline investigational strategies at the intersection of geroscience and oncology, including immune engineering, senolytics, microenvironmental modulation, and AI-driven multi-omic modeling. Overall, this review argues that biological age represents a critical but still underdeveloped dimension of precision oncology, and highlights key evidence gaps that must be addressed before age-aware personalization can be implemented in routine lung cancer care.

PMID:41821888 | PMC:PMC12975599 | DOI:10.3389/fonc.2026.1743620

Am J Surg Pathol. 2026 Mar 13. doi: 10.1097/PAS.0000000000002533. Online ahead of print.

ABSTRACT

With the application of molecular techniques in pathologic diagnosis, several novel primary pulmonary epithelial tumors have been continuously discovered and classified under the WHO classification of thoracic tumors. Recently, a pulmonary tumor with NFATC2::NUTM2B fusion was first documented, but the spectrum of NFATC2::NUTM2 fusion variants and their associated pathologic features remains incompletely characterized. Coincidentally, we also found and described 6 primary pulmonary tumors harboring recurrent NFATC2::NUTM2A/E fusions through integrated genomic analysis. These patients, including 4 females and 2 males, with a median age of 53 years, presented with incidentally detected peripheral lung nodules composed of monotonous epithelioid cells arranged in cords, nests, and trabeculae within a prominent desmoplastic stroma. All tumors exhibited a consistent immunophenotype: CK5/6+/GATA3+/calponin+/EMA+/DOG1 (perinuclear dot-like staining)/p63-. High-throughput chromosome conformation capture (Hi-C) analysis showed the structural variation of NFATC2::NUTM2E in all 6 cases, whereas RNA sequencing detected the fusion transcripts in 5 cases (NFATC2::NUTM2A, n=2; NFATC2::NUTM2E, n=3). Ultrastructural examination of 1 case suggested epithelial differentiation. All patients remained disease-free after complete resection (median follow-up: 24 mo; range: 9 to 41 mo). These findings define a novel primary pulmonary tumor entity driven by NFATC2::NUTM2 fusions, and characterized by a distinctive immunophenotype, expanding the spectrum of NUTM2-associated neoplasms. Our study underscores the utility of multiomics approaches for characterizing rare neoplasms and provides a diagnostic framework for this entity.

PMID:41821426 | DOI:10.1097/PAS.0000000000002533

Nat Commun. 2026 Mar 12. doi: 10.1038/s41467-026-70376-5. Online ahead of print.

ABSTRACT

Myasthenia gravis (MG) is an autoimmune disorder characterized by impaired neuromuscular transmission and motor symptoms. Its genetic background remains unclear, particularly beyond specific subtypes reported in European populations. Here, we perform a genome-wide association study (GWAS) of 1,434 MG cases covering all disease subtypes and 42,913 controls of Japanese, which newly identify the TERT locus (odds ratio [OR] = 1.31, P = 1.7×10^-10). Subtype-stratified GWASs show stronger signals for generalized MG (gMG; OR = 1.38, P = 1.6×10^-12), anti AChR antibody-positive gMG (g-AChR-Ab(+)MG; OR= 1.49, P = 2.1×10^-15), and thymoma-associated gMG (g-TAMG; OR = 1.92, P = 1.1×10^-15). Fine-mapping of the major histocompatibility complex region reveal distinct associations of HLA-DRB1 with late onset gMG (g-LOMG) and HLA-A with early onset gMG (g-EOMG). The MG risk TERT lead variant rs2736099 is associated with poor treatment response, especially in g-AChR-Ab(+)MG and g-EOMG (P < 0.0042). The biobank-based phenome-wide association study identify pleiotropic effects on lung cancer, hematological traits, and telomere length. Single cell transcriptomics and immunohistochemistry identified immature lymphocyte-specific TERT expression in thymoma specimens. Full-length transcriptomics reveal allele-specific decreasing effect of rs2736099-A on TERT expression. Our study unveils genetics of MG distinctly across disease subtypes, and involvement of TERT in its pathogenesis.

PMID:41820352 | DOI:10.1038/s41467-026-70376-5

Transl Cancer Res. 2026 Feb 28;15(2):77. doi: 10.21037/tcr-2025-aw-2179. Epub 2026 Feb 11.

ABSTRACT

BACKGROUND: Hepatocellular carcinoma (HCC) exhibits notable characteristics, encompassing frequent recurrence, weak immunotherapeutic outcomes and unfavorable prognosis. BTF3L4 has been identified as a critical factor in the progression of various malignancies. However, its specific role in HCC remains to be elucidated. This investigation sought to examine BTF3L4 levels in HCC and BTF3L4's connection with clinical prognosis and immune infiltration.

METHODS: We performed an extensive multi-omics evaluation in the course of our research. Bioinformatics tools were utilized to assess BTF3L4 messenger RNA (mRNA) expression in HCC. Multiplex immunohistochemistry (mIHC) was utilized to examine BTF3L4 protein expression and to explore its correlation with tumor-infiltrating immune cells (TIICs). Cox regression analysis and Kaplan-Meier survival curves were applied to determine BTF3L4's impact on patient outcomes.

RESULTS: Our analysis revealed markedly elevated levels of both BTF3L4 mRNA and protein in HCC tissues. BTF3L4 protein abundance emerged as an independent predictor of reduced survival in patients with HCC. Furthermore, elevated BTF3L4 protein expression was positively associated with cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) expression and markedly negatively correlated with CD4⁺ T cells and CD66b⁺ neutrophils in HCC tissues.

CONCLUSIONS: This evidence indicates that BTF3L4 functions as a predictive indicator and is a potential candidate for HCC immunotherapy.

PMID:41815168 | PMC:PMC12971597 | DOI:10.21037/tcr-2025-aw-2179