Reading view
DBPnet: Damper Characteristics-Based Bayesian Physics-Informed Neural Network for Wheel Load Estimation
Hide to Guide: Learning via Semantic Masking
Benchmarking Pathology Foundation Models for Spatial Domain Understanding
Topology-Driven Transferability Estimation of Medical Foundation Models for Segmentation
Integrative multi-omics and experimental validation reveal UBE2C as a central hub gene and prognostic biomarker in hepatocellular carcinoma
Int Immunopharmacol. 2026 May 19;183:116866. doi: 10.1016/j.intimp.2026.116866. Online ahead of print.
ABSTRACT
Hepatocellular carcinoma (HCC) is a lethal malignancy with a high recurrence rate and limited treatment options. Ubiquitin-conjugating enzyme E2 C (UBE2C) is implicated in various cancers, yet its impact on the HCC immune landscape remains incompletely understood. Herein, hub genes in HCC were identified, by integrating co-expression networks and protein-protein interaction analyses, from the TCGA, GEO, and CPTAC databases. Their expression was analysed using a single-cell transcriptomic database and verified in HCC tissues and cell lines via quantitative reverse transcription-PCR and immunoblotting. Functional roles of UBE2C were assessed using in vitro knockdown experiments and an in vivo subcutaneous tumour model. The tumour immune microenvironment was profiled using spatial transcriptomics, RNA-seq data, and ssGSEA. A prognostic nomogram was constructed based on multivariate Cox regression. UBE2C was identified as a significantly upregulated hub gene in HCC. Single-cell RNA-seq revealed predominant expression of UBE2C in hepatocytes, with dynamic upregulation along differentiation trajectories. UBE2C knockdown suppressed proliferation, induced apoptosis, and inhibited tumour growth. Spatial transcriptomics highlighted UBE2C-high regions within proliferative niches exhibiting immunosuppressive traits-including TGFB1 enrichment, impaired CXCL9-CXCR3 signalling, and exclusion of cytotoxic T cells-which were reduced in immunotherapy responders. UBE2C expression correlated with immune checkpoint genes and specific immune cell subsets. A UBE2C-based nomogram integrating T stage and tumour stage robustly predicted patient survival, and miR-300 and miR-381-3p were identified as potential upstream regulators. These findings establish UBE2C as a key driver of HCC progression and a biomarker for prognosis and immunotherapy stratification.
PMID:42155390 | DOI:10.1016/j.intimp.2026.116866
UBTF-HSP90A-MIF stress circuit drives lenvatinib resistance and immune exclusion in hepatocellular carcinoma
J Adv Res. 2026 Apr 5:S2090-1232(26)00280-8. doi: 10.1016/j.jare.2026.04.002. Online ahead of print.
ABSTRACT
INTRODUCTION: The clinical benefit of combining lenvatinib with PD-1 blockade in HCC is frequently constrained by adaptive resistance and the development of an immune-cold tumor microenvironment.
OBJECTIVES: This study aimed to elucidate the molecular mechanisms underlying adaptive resistance and immune exclusion during lenvatinib-PD-1 therapy in HCC, with a particular focus on a UBTF/HSP90A/MIF regulatory circuit. We examined whether genetic or pharmacologic targeting of macrophage migration inhibitory factor (MIF) could restore lenvatinib sensitivity, remodel the tumor immune microenvironment, and serve as a predictive biomarker in clinical cohorts.
METHODS: Paired lenvatinib-sensitive and -resistant HCC models were interrogated using integrated multi-omic and functional approaches, including RNA sequencing, promoter pull-down assays, ChIP, luciferase reporter assays, PLA, and flow cytometry. Key findings were validated in patient-derived organoids and xenografts, as well as in an immunocompetent hydrodynamic HCC mouse model. Clinical relevance was evaluated in independent cohorts treated with lenvatinib plus anti-PD-1 therapy.
RESULTS: UBTF directly bound to and transcriptionally activated the HSP90A promoter, resulting in increased HSP90A expression and stabilization of MIF. MIF signaling through CD74 co-activated the PI3K-AKT and MAPK pathways, sustaining tumor cell proliferation under lenvatinib pressure. Single-cell RNA sequencing and multiplex immunohistochemistry revealed macrophage enrichment and CD8+ T-cell exclusion in resistant tumors. Genetic ablation of Mif (Alb-Cre; Mifflox/flox) or pharmacologic inhibition with 4-IPP (4-Iodo-6-phenylpyrimidine) restored lenvatinib sensitivity, reprogrammed the tumor immune microenvironment, and, when combined with PD-1 blockade, achieved superior tumor control and prolonged survival. In clinical datasets, low pretreatment MIF expression was associated with improved responses to lenvatinib plus PD-1 therapy.
CONCLUSIONS: These findings define a UBTF/HSP90A/MIF axis linking proteostasis and cytokine signaling to immune-metabolic dysfunction and lenvatinib resistance in HCC. MIF emerges as both a mechanistic driver and a predictive biomarker, supporting prospective evaluation of therapeutic strategies combining lenvatinib-PD-1 with MIF- or HSP90A-targeted interventions to personalize TKI-ICI therapy.
PMID:41946392 | DOI:10.1016/j.jare.2026.04.002
Protective Effects of the Ethyl Acetate Fraction from Madeng'ai on Lipopolysaccharide-Induced Acute Lung Injury in Mice: Insights from Integrated Multi-Omics Analysis
J Ethnopharmacol. 2026 Apr 4:121650. doi: 10.1016/j.jep.2026.121650. Online ahead of print.
ABSTRACT
ETHNOPHARMACOLOGICAL RELEVANCE: Madeng'ai (MDA) is a traditional medicinal plant of the Dong ethnic group. Its roots have been widely used in folk medicine for clearing heat and removing toxins, alleviating swelling and relieving pain, dispersing blood stasis and arresting bleeding, as well as promoting wound healing. It is taxonomically classified as a variety of Potentilla freyniana Bornm.
AIM OF THE STUDY: Acute lung injury (ALI) is a life-threatening pulmonary disorder associated with high mortality, underscoring the urgent need to explore novel therapeutic strategies. This study aimed to evaluate the protective effects of the ethyl acetate fraction of MDA (MEA) against LPS-induced ALI in mice and to investigate its underlying mechanisms.
MATERIALS AND METHODS: LC-MS/MS was employed to tentatively identify the bioactive components of MEA. A mouse model of ALI was established by LPS induction. The protective effects of MEA were evaluated through assessments of lung histopathology, inflammatory cytokine levels, and oxidative stress markers. The underlying mechanisms were systematically investigated by integrating transcriptomics, metabolomics, network pharmacology, molecular docking, and Western blotting.
RESULTS: MEA significantly attenuated LPS-induced pulmonary pathological lesions, pulmonary edema, and excessive inflammatory responses in ALI mice. Comprehensive bioinformatics analyses predicted potential mechanisms involving oxidative stress and the regulation of metabolic pathways. Experimental validation via Western blotting confirmed that MEA inhibited TLR4-mediated inflammatory signaling and modulated the PI3K/AKT pathway, thereby exerting multi-pathway protective effects against ALI.
CONCLUSIONS: Collectively, this study confirms that MEA, as a traditional herbal extract, holds potential as an adjuvant therapeutic agent for ALI, providing experimental evidence for the modernization and development of ethnic medicines.
PMID:41941987 | DOI:10.1016/j.jep.2026.121650
Protective Effects of the Ethyl Acetate Fraction from Madeng'ai on Lipopolysaccharide-Induced Acute Lung Injury in Mice: Insights from Integrated Multi-Omics Analysis
J Ethnopharmacol. 2026 Apr 4:121650. doi: 10.1016/j.jep.2026.121650. Online ahead of print.
ABSTRACT
ETHNOPHARMACOLOGICAL RELEVANCE: Madeng'ai (MDA) is a traditional medicinal plant of the Dong ethnic group. Its roots have been widely used in folk medicine for clearing heat and removing toxins, alleviating swelling and relieving pain, dispersing blood stasis and arresting bleeding, as well as promoting wound healing. It is taxonomically classified as a variety of Potentilla freyniana Bornm.
AIM OF THE STUDY: Acute lung injury (ALI) is a life-threatening pulmonary disorder associated with high mortality, underscoring the urgent need to explore novel therapeutic strategies. This study aimed to evaluate the protective effects of the ethyl acetate fraction of MDA (MEA) against LPS-induced ALI in mice and to investigate its underlying mechanisms.
MATERIALS AND METHODS: LC-MS/MS was employed to tentatively identify the bioactive components of MEA. A mouse model of ALI was established by LPS induction. The protective effects of MEA were evaluated through assessments of lung histopathology, inflammatory cytokine levels, and oxidative stress markers. The underlying mechanisms were systematically investigated by integrating transcriptomics, metabolomics, network pharmacology, molecular docking, and Western blotting.
RESULTS: MEA significantly attenuated LPS-induced pulmonary pathological lesions, pulmonary edema, and excessive inflammatory responses in ALI mice. Comprehensive bioinformatics analyses predicted potential mechanisms involving oxidative stress and the regulation of metabolic pathways. Experimental validation via Western blotting confirmed that MEA inhibited TLR4-mediated inflammatory signaling and modulated the PI3K/AKT pathway, thereby exerting multi-pathway protective effects against ALI.
CONCLUSIONS: Collectively, this study confirms that MEA, as a traditional herbal extract, holds potential as an adjuvant therapeutic agent for ALI, providing experimental evidence for the modernization and development of ethnic medicines.
PMID:41941987 | DOI:10.1016/j.jep.2026.121650
Scale over Preference: The Impact of AI-Generated Content on Online Content Ecology
VectorGym: A Multitask Benchmark for SVG Code Generation, Sketching, and Editing
TRIM21-mediated degradation of HILPDA overcomes anti-PD-1 immunotherapy resistance in breast cancer by limiting PD-L1 palmitoylation
Oncogene, Published online: 24 March 2026; doi:10.1038/s41388-026-03728-6
TRIM21-mediated degradation of HILPDA overcomes anti-PD-1 immunotherapy resistance in breast cancer by limiting PD-L1 palmitoylationComputational analysis of multi-omics data reveals CXCL10(+) DC-Treg interaction drives immunosuppressive microenvironment in AFP-positive hepatocellular carcinoma
Cell Mol Life Sci. 2026 Mar 19. doi: 10.1007/s00018-026-06167-4. Online ahead of print.
NO ABSTRACT
PMID:41854876 | DOI:10.1007/s00018-026-06167-4
OpenSage: Self-programming Agent Generation Engine
HKDC1-Mediated Polyamine Rewiring Drives Lenvatinib Resistance and Immune Escape in Hepatocellular Carcinoma
Clin Mol Hepatol. 2026 Mar 11. doi: 10.3350/cmh.2025.1269. Online ahead of print.
ABSTRACT
BACKGROUND/AIMS: Lenvatinib resistance and immune exclusion limit outcomes in HCC. We hypothesized that metabolic rewiring orchestrates resistance to lenvatinib and PD-1 blockade.
METHODS: We established LS/LR HCC models and employed multi-omics (proteomics/RNA-seq), ChIP, luciferase, and RIP assays to map HKDC1 regulation. Tumor immunity was profiled by scRNA-seq, mIHC, and flow cytometry. SPD + lenvatinib efficacy was tested in cell lines, patient-derived organoids/xenografts. Tested therapy effect in an immunocompetent hydrodynamic HCC model with hepatocyte-specific Hkdc1 deletion; and analyzed a postoperative cohort (n = 40) treated with lenvatinib + PD-1.
RESULTS: HKDC1, upregulated in LR HCC, was transcriptionally activated by USF1 and promoted SMS-mediated polyamine rewiring. This impaired CD8⁺ T-cell metabolism, reversible by HKDC1 knockdown or spermidine (SPD). SPD synergized with lenvatinib, triggering autophagy and suppressing tumor growth in vitro and in vivo. High HKDC1 predicted poor response and survival in patients receiving lenvatinib + aPD-1.
CONCLUSIONS: A USF1/HKDC1/SMS axis couples polyamine metabolism to immune dysfunction and lenvatinib resistance. HKDC1 is a predictive biomarker and therapeutic node and support polyamine-axis modulation to sensitize HCC to lenvatinib plus PD-1 therapy.
PMID:41812646 | DOI:10.3350/cmh.2025.1269