Signal Transduct Target Ther. 2026 Sep 28;11(1):418. doi: 10.1038/s41392-026-02875-2.

ABSTRACT

Hepatocellular carcinoma (HCC) exhibits a suboptimal response to immune checkpoint blockade (ICB) therapy; to overcome this resistance, we aimed to delineate key immune resistance factors via multi-omics analysis, develop strategies to block their immunosuppressive axes, and engineer a targeted nanosystem to enhance immunotherapy efficacy against PD-1 resistance in HCC. Using transcriptomic and proteomic data from anti-PD-1-treated HCC patients, along with functional validation in murine models and mechanistic molecular and cell biology studies, we identified transketolase-like 1 (TKTL1) as a dual-nature biomarker where overexpression predicted poor baseline prognosis yet enhanced response to ICB. Mechanistically, TKTL1 diverts glucose flux into glycolysis rather than pentose phosphate pathway (PPP), recruiting USP9X to deubiquitinate and stabilize HIF-1α, which upregulates HK2 to amplify glycolytic output and lactate accumulation. This metabolic rewiring orchestrates dual immunosuppressive circuits through HIF-1α-driven CCL4 secretion recruiting PD-L1^high dendritic cells (DCs), coupled with lactate-induced TRIM28^K408 lactylation that stabilizes PD-L1 by blocking ubiquitin-mediated degradation. We engineered a hepatoma-membrane-coated MnO₂ nanosystem (CQLH) co-delivering a TKTL1 inhibitor and lactate oxidase, which disrupted the TKTL1-HIF-1α-HK2 axis, depleted lactate, and reprogrammed the tumor microenvironment, thereby enhanced anti-PD-1 therapy to suppress tumor growth, especially in TKTL1^high tumors. These findings define a critical "TKTL1-glycolysis-lactate-DC" axis driving anti-PD-1 sensitivity in HCC, position TKTL1 as both a potential biomarker for ICB response and a tractable therapeutic target, and demonstrate that the targeted CQLH nanosystem overcomes resistance and enhances anti-PD-1 efficacy, offering a precision immunotherapeutic strategy for TKTL1^high HCC.

PMID:42802226 | PMC:PMC13616917 | DOI:10.1038/s41392-026-02875-2

Ecotoxicol Environ Saf. 2026 May 25;319:120306. doi: 10.1016/j.ecoenv.2026.120306. Online ahead of print.

ABSTRACT

The respiratory toxicity of heated tobacco products (HTPs) remains incompletely characterized, and traditional models often fail to capture human-specific responses. Here, we established a human pluripotent stem cell (hPSC)-derived airway organoid (AO) platform and systematically compared the toxicological profiles of two HTP aerosols using an integrated framework encompassing conventional cytotoxicity assays, lineage-specific analysis, network perturbation modeling and multi-omics profiling. Both HTPs induced time- and concentration-dependent cytotoxicity, oxidative stress, DNA damage, and apoptosis in AOs. Exposure also triggered epithelial chemokine response characterized by elevated IL-8, MCP-1, MIP-1β, GM-CSF, and RANTES, with concomitant suppression of IP-10, indicating epithelial-derived inflammatory alarm signals. Lineage-specific transcriptional changes revealed mucociliary dysfunction characterized by goblet cell hyperplasia (MUC5AC upregulation) and ciliated cell impairment (FOXJ1 downregulation), key features of airway remodeling in chronic respiratory diseases. To delineate underlying mechanisms, we employed Network Perturbation Amplitude (NPA) analysis, which uncovered qualitatively distinct toxicity architectures: HTP-1 exhibited higher overall toxicity and elicited broad-spectrum network perturbations involving cell stress, proliferation, and immune regulation, correlating with greater apoptotic induction; HTP-2 triggered focused activation of damage-sensing pathways, consistent with its earlier membrane disruption and more pronounced genotoxicity. Multi-omics analysis further linked these mechanistic perturbations to human disease-relevant pathways, with HTP-1 showing stronger enrichment for COPD-associated expression patterns and HTP-2 for lung cancer-related signatures, suggesting the acute molecular response to each product exhibits similarity to specific pulmonary disease-associated molecular signatures. These findings establish human-derived airway organoids as a sensitive, human-relevant platform within the New Approach Methodologies‌ (NAMs) framework for qualitative comparison and mechanistic interrogation of product-specific toxicity.

PMID:42184653 | DOI:10.1016/j.ecoenv.2026.120306

Ecotoxicol Environ Saf. 2026 May 25;319:120306. doi: 10.1016/j.ecoenv.2026.120306. Online ahead of print.

ABSTRACT

The respiratory toxicity of heated tobacco products (HTPs) remains incompletely characterized, and traditional models often fail to capture human-specific responses. Here, we established a human pluripotent stem cell (hPSC)-derived airway organoid (AO) platform and systematically compared the toxicological profiles of two HTP aerosols using an integrated framework encompassing conventional cytotoxicity assays, lineage-specific analysis, network perturbation modeling and multi-omics profiling. Both HTPs induced time- and concentration-dependent cytotoxicity, oxidative stress, DNA damage, and apoptosis in AOs. Exposure also triggered epithelial chemokine response characterized by elevated IL-8, MCP-1, MIP-1β, GM-CSF, and RANTES, with concomitant suppression of IP-10, indicating epithelial-derived inflammatory alarm signals. Lineage-specific transcriptional changes revealed mucociliary dysfunction characterized by goblet cell hyperplasia (MUC5AC upregulation) and ciliated cell impairment (FOXJ1 downregulation), key features of airway remodeling in chronic respiratory diseases. To delineate underlying mechanisms, we employed Network Perturbation Amplitude (NPA) analysis, which uncovered qualitatively distinct toxicity architectures: HTP-1 exhibited higher overall toxicity and elicited broad-spectrum network perturbations involving cell stress, proliferation, and immune regulation, correlating with greater apoptotic induction; HTP-2 triggered focused activation of damage-sensing pathways, consistent with its earlier membrane disruption and more pronounced genotoxicity. Multi-omics analysis further linked these mechanistic perturbations to human disease-relevant pathways, with HTP-1 showing stronger enrichment for COPD-associated expression patterns and HTP-2 for lung cancer-related signatures, suggesting the acute molecular response to each product exhibits similarity to specific pulmonary disease-associated molecular signatures. These findings establish human-derived airway organoids as a sensitive, human-relevant platform within the New Approach Methodologies‌ (NAMs) framework for qualitative comparison and mechanistic interrogation of product-specific toxicity.

PMID:42184653 | DOI:10.1016/j.ecoenv.2026.120306

Cancer Cell Int. 2026 May 14. doi: 10.1186/s12935-026-04330-2. Online ahead of print.

ABSTRACT

BACKGROUND: Liver hepatocellular carcinoma (LIHC) is a common malignancy, yet the core genes driving its progression and potential therapeutic targets remain insufficiently explored. Ribosome biogenesis (RB) is a critical biological process linked to various cancers; however, its systematic role in LIHC remains unclear.

METHODS: This study integrated LIHC single-cell RNA-Seq, bulk RNA-Seq, and spatial transcriptomic data with ribosome biogenesis-related gene sets to construct a single-cell atlas of LIHC. Weighted Gene Co-expression Network Analysis (WGCNA) was employed to characterize myeloid cell subsets. Furthermore, an LIHC prognostic risk model based on RB-related genes was developed using 117 machine-learning algorithm combinations. Key findings were subsequently corroborated through experimental validation and clinical sample analysis.

RESULTS: We identified a distinct macrophage subpopulation with high ribosome biogenesis activity, termed ribosome biogenesis-active macrophages (RAMs). These cells exhibited strong communication with inflammatory macrophages, potentially mediated by MIF-related receptor-ligand interactions. We further constructed an 8-gene prognostic model (PA2G4, GNL2, PWP1, DDX49, NOC4L, GDI2, CST7, and RCL1), which showed good predictive performance. Drug sensitivity analysis suggested that the high-risk group may be more responsive to several agents, including docetaxel. Among these genes, GNL2 was selected for further investigation. Elevated GNL2 expression was associated with increased stemness features in myeloid cells. Molecular docking analysis identified several candidate compounds with potential binding affinity to GNL2. Functionally, GNL2 knockdown in macrophages reduced TGF-β and TNF-α expression and was associated with decreased proliferation, migration, and invasion of LIHC cells.

CONCLUSION: We identified a highly active ribosome biogenesis-macrophage subpopulation (RAM), and constructed a robust risk model to aid in the diagnosis, prognosis, and treatment of LIHC. GNL2 is associated with increased expression of TGF-β and TNF-α and may contribute to LIHC progression.

PMID:42135716 | DOI:10.1186/s12935-026-04330-2

Gut. 2026 Feb 9;75(3):576-587. doi: 10.1136/gutjnl-2025-337506.

ABSTRACT

BACKGROUND: Current guidelines recommend a two-step approach for risk stratification of metabolic dysfunction-associated steatotic liver disease (MASLD), starting with Fibrosis-4 index (FIB-4) followed by liver stiffness measurement (LSM) using vibration-controlled transient elastography (VCTE).

OBJECTIVE: To evaluate this approach for predicting advanced fibrosis and liver-related events (LREs) in patients with type 2 diabetes (T2D).

DESIGN: A prospective liver biopsy cohort of T2D patients with histologically confirmed MASLD from seven centres in China was used to assess diagnostic performance for advanced fibrosis. The international VCTE-Prognosis cohort, including T2D patients with MASLD who underwent VCTE at 16 centres in the USA, Europe and Asia, with longitudinal follow-up, was used to assess LREs, defined as hepatic decompensation or hepatocellular carcinoma.

RESULTS: 4781 participants were included. In the liver biopsy cohort (n=352; 22.2% with advanced fibrosis), applying LSM thresholds of <8 kPa and >12 kPa after FIB-4 classified patients into 63.4% low-risk, 9.4% intermediate-risk and 27.3% high-risk, with a correct classification rate of 71%. In the VCTE-Prognosis cohort (n=4429; median follow-up 51.3 (IQR 27.4-70.7) months), 140 (3.2%) patients developed LREs (110 (2.5%) with hepatic decompensation and 59 (1.3%) with hepatocellular carcinoma). The two-step approach classified 72.6%, 6.8% and 20.6% of patients into low-risk, intermediate-risk and high-risk groups, with corresponding 5-year cumulative LRE incidences of 0.7%, 0.9% and 11.8%. Refining classification of intermediate FIB-4 patients using LSM <10 kPa (low-risk) and >15 kPa (high-risk) reduced the intermediate-risk group to 5.6% while preserving predictive accuracy.

CONCLUSION: The non-invasive two-step approach of FIB-4 followed by LSM effectively stratifies MASLD-related advanced fibrosis and LREs risk in T2D. Applying LSM cut-offs of 10 and 15 kPa further optimises risk stratification for future LREs.

PMID:41911049 | DOI:10.1136/gutjnl-2025-337506

J Proteome Res. 2026 Apr 3;25(4):2014-2023. doi: 10.1021/acs.jproteome.5c00983. Epub 2026 Mar 17.

ABSTRACT

OBJECTIVE: 19-Hydroxybufalin (19-H) is a natural bioactive compound with anticancer potential, but its molecular target and mechanism of action remain unclear. This study aimed to systematically evaluate its antigastric cancer activity and identify potential molecular targets.

METHODS: The antitumor effect of 19-H was evaluated in both in vitro and in vivo models. Multiomics analysis, thermal proteome profiling, molecular docking, and molecular dynamics simulations were employed to elucidate the mechanism of action. Functional assays were further conducted to validate the key target.

RESULTS: 19-H exhibited nanomolar-level inhibitory activity against various gastric cancer cell lines, significantly suppressing tumor growth in subcutaneous xenograft and patient-derived xenograft models. Multiomics analysis revealed that 19-H reshaped metabolic pathways in gastric cancer. TPP screening identified PLPP2 as a potential target with significantly increased thermal stability upon 19-H treatment. Molecular simulations further revealed that 19-H binds stably to the α-helical region of PLPP2.

CONCLUSIONS: 19-H exerts its antigastric cancer effect by targeting PLPP2 and remodeling the metabolic network. PLPP2 may represent a novel therapeutic target for gastric cancer.

PMID:41842934 | DOI:10.1021/acs.jproteome.5c00983