Int J Mol Sci. 2026 Feb 25;27(5):2170. doi: 10.3390/ijms27052170.

ABSTRACT

Carbosulfan is a widely used carbamate insecticide, yet its mechanisms of respiratory toxicity remain poorly understood. This study integrated network toxicology, untargeted metabolomics, and molecular docking to systematically investigate the potential mechanisms of carbosulfan-induced respiratory toxicity in male Sprague Dawley rats. Rats were administered a single oral dose of carbosulfan (125 or 250 mg/kg) and assessed after 12 h. Exposure resulted in significant pathological lung damage, characterized by disrupted alveolar architecture, inflammatory cell infiltration, and increased serum levels of the pro-inflammatory cytokines IL-6, IL-1β, and TNF-α. Network toxicology analysis identified 51 potential targets associated with respiratory toxicity, with core targets including SRC, EGFR, PTGS2, CXCL8, CYP3A4, and NR3C1. Enriched pathways were primarily related to neuroactive ligand-receptor interaction, VEGF signaling, and arachidonic acid metabolism. Untargeted metabolomics revealed significant metabolic perturbations in pathways central to antioxidant defense and energy homeostasis, including glutathione metabolism, the tricarboxylic acid cycle, and arginine biosynthesis. Molecular docking confirmed stable in silico binding affinities between carbosulfan and the predicted core targets. Integrative analysis suggests that carbosulfan exposure is associated with respiratory damage, potentially through interconnected mechanisms involving oxidative stress, inflammation, and disruption of cell signaling and metabolic enzyme systems. However, given the acute high-dose nature of the model and the interpretative integration of multi-omics data, these findings should be considered hypothesis-generating. This study provides a novel system-level perspective on carbosulfan-induced respiratory toxicity and highlights key pathways and targets for future validation in chronic exposure models.

PMID:41828400 | PMC:PMC12984169 | DOI:10.3390/ijms27052170

Int J Mol Sci. 2026 Feb 25;27(5):2170. doi: 10.3390/ijms27052170.

ABSTRACT

Carbosulfan is a widely used carbamate insecticide, yet its mechanisms of respiratory toxicity remain poorly understood. This study integrated network toxicology, untargeted metabolomics, and molecular docking to systematically investigate the potential mechanisms of carbosulfan-induced respiratory toxicity in male Sprague Dawley rats. Rats were administered a single oral dose of carbosulfan (125 or 250 mg/kg) and assessed after 12 h. Exposure resulted in significant pathological lung damage, characterized by disrupted alveolar architecture, inflammatory cell infiltration, and increased serum levels of the pro-inflammatory cytokines IL-6, IL-1β, and TNF-α. Network toxicology analysis identified 51 potential targets associated with respiratory toxicity, with core targets including SRC, EGFR, PTGS2, CXCL8, CYP3A4, and NR3C1. Enriched pathways were primarily related to neuroactive ligand-receptor interaction, VEGF signaling, and arachidonic acid metabolism. Untargeted metabolomics revealed significant metabolic perturbations in pathways central to antioxidant defense and energy homeostasis, including glutathione metabolism, the tricarboxylic acid cycle, and arginine biosynthesis. Molecular docking confirmed stable in silico binding affinities between carbosulfan and the predicted core targets. Integrative analysis suggests that carbosulfan exposure is associated with respiratory damage, potentially through interconnected mechanisms involving oxidative stress, inflammation, and disruption of cell signaling and metabolic enzyme systems. However, given the acute high-dose nature of the model and the interpretative integration of multi-omics data, these findings should be considered hypothesis-generating. This study provides a novel system-level perspective on carbosulfan-induced respiratory toxicity and highlights key pathways and targets for future validation in chronic exposure models.

PMID:41828400 | PMC:PMC12984169 | DOI:10.3390/ijms27052170

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

Crit Care Explor. 2026 Mar 12;8(3):e1390. doi: 10.1097/CCE.0000000000001390. eCollection 2026 Mar 1.

ABSTRACT

IMPORTANCE: Inflammation, endothelial dysfunction, and complement activation are associated with COVID-19 acute lung injury (ALI) and acute respiratory distress syndrome (ARDS).

OBJECTIVES: We hypothesized that higher levels of inflammation, endothelial dysfunction, and complement activation implicated in more severe COVID-19 ALI/ARDS are associated with post-acute sequelae of COVID-19 (PASC) phenotypes in the 3 years after hospitalization.

DESIGN, SETTING, AND PARTICIPANTS: A single-center prospective cohort of 150 adult survivors of severe and critical COVID-19 from the first wave of the pandemic with sampling weighted to include 50% survivors of mechanical ventilation.

MAIN OUTCOMES AND MEASURES: Eleven serum biomarkers at hospital discharge, 4 months, 15 months, and 3 years, and symptoms and physical function at 15 months and 3 years. PASC presence was defined using the 12 symptoms and scoring from the Researching COVID to Enhance Recovery (RECOVER) definition. We tested associations of biomarkers with PASC and symptom phenotypes of post-exertional malaise, fatigue, and brain fog while adjusting for age, sex, body mass index, comorbidities, and days since COVID-19 diagnosis.

RESULTS: The mean (sd) age of the cohort was 56 years (13); 67% were Hispanic and 25% were Black. PASC was present in 26% of participants at both 15 months and 3 years. PASC and symptom phenotypes at 15 months and 3 years were consistently associated with higher frailty phenotype category, worse short physical performance battery scores, and shorter 6-minute walk distance. Biomarkers of inflammation, including interleukin-6 and soluble tumor necrosis factor receptor-1, endothelial function, including angiopoietin, and complement, including C2, C4b, and C5, were not associated with PASC or symptom phenotypes in cross-sectional or longitudinal analyses.

CONCLUSIONS AND RELEVANCE: PASC persists for 3 years after acute COVID-19 ALI/ARDS, is associated with frailty, but not associated with persistently higher levels of inflammatory, endothelial, and complement biomarkers implicated in worse short-term outcomes in acute COVID-19, non-COVID-19 ARDS, and sepsis. Future studies should employ multiomics to elucidate potential mechanisms of PASC.

PMID:41824803 | DOI:10.1097/CCE.0000000000001390

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

Crit Care Explor. 2026 Mar 12;8(3):e1390. doi: 10.1097/CCE.0000000000001390. eCollection 2026 Mar 1.

ABSTRACT

IMPORTANCE: Inflammation, endothelial dysfunction, and complement activation are associated with COVID-19 acute lung injury (ALI) and acute respiratory distress syndrome (ARDS).

OBJECTIVES: We hypothesized that higher levels of inflammation, endothelial dysfunction, and complement activation implicated in more severe COVID-19 ALI/ARDS are associated with post-acute sequelae of COVID-19 (PASC) phenotypes in the 3 years after hospitalization.

DESIGN, SETTING, AND PARTICIPANTS: A single-center prospective cohort of 150 adult survivors of severe and critical COVID-19 from the first wave of the pandemic with sampling weighted to include 50% survivors of mechanical ventilation.

MAIN OUTCOMES AND MEASURES: Eleven serum biomarkers at hospital discharge, 4 months, 15 months, and 3 years, and symptoms and physical function at 15 months and 3 years. PASC presence was defined using the 12 symptoms and scoring from the Researching COVID to Enhance Recovery (RECOVER) definition. We tested associations of biomarkers with PASC and symptom phenotypes of post-exertional malaise, fatigue, and brain fog while adjusting for age, sex, body mass index, comorbidities, and days since COVID-19 diagnosis.

RESULTS: The mean (sd) age of the cohort was 56 years (13); 67% were Hispanic and 25% were Black. PASC was present in 26% of participants at both 15 months and 3 years. PASC and symptom phenotypes at 15 months and 3 years were consistently associated with higher frailty phenotype category, worse short physical performance battery scores, and shorter 6-minute walk distance. Biomarkers of inflammation, including interleukin-6 and soluble tumor necrosis factor receptor-1, endothelial function, including angiopoietin, and complement, including C2, C4b, and C5, were not associated with PASC or symptom phenotypes in cross-sectional or longitudinal analyses.

CONCLUSIONS AND RELEVANCE: PASC persists for 3 years after acute COVID-19 ALI/ARDS, is associated with frailty, but not associated with persistently higher levels of inflammatory, endothelial, and complement biomarkers implicated in worse short-term outcomes in acute COVID-19, non-COVID-19 ARDS, and sepsis. Future studies should employ multiomics to elucidate potential mechanisms of PASC.

PMID:41824803 | PMC:PMC12987405 | DOI:10.1097/CCE.0000000000001390

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

Front Cell Infect Microbiol. 2026 Feb 23;16:1732958. doi: 10.3389/fcimb.2026.1732958. eCollection 2026.

ABSTRACT

INTRODUCTION: Lung adenocarcinoma (LUAD), the most common subtype of non-small cell lung cancer, is a form of malignant pulmonary nodule that requires clinical differentiation from benign pulmonary nodules (BPN). The mechanisms underlying the development of LUAD are complex, and effective non-invasive methods for differentiating BPN from LUAD are lacking. This study aimed not only to distinguish BPN from LUAD using gut fungi and serum metabolites, but also to establish an integrated network of gut fungi-metabolite-cytokine interactions.

METHODS: Fecal and serum samples from individuals with BPN and patients with LUAD were subjected to internal transcribed spacer sequencing, ultra-performance liquid chromatography-tandem mass spectrometry, and multiplex Luminex assays to quantify gut fungi, metabolites, and cytokines, respectively.

RESULTS: A significant difference in gut fungal communities was observed between the BPN and LUAD groups. Multiple genera and species were more abundant in LUAD than in BPN. Docosapentaenoic acid n-6 (DPAn-6), indole-3-propionic acid (IPA), and interferon-γ-induced protein 10 (IP-10) were significantly elevated in the LUAD group. The integrated model established using a combination of gut fungi and metabolites demonstrated excellent performance in distinguishing BPN from LUAD. A network of interactions was established among differentially abundant gut fungi, serum metabolites, and cytokines.

CONCLUSION: Our study identifies a novel panel of fungal and metabolite biomarkers for differentiating between BPN and LUAD, and constructs a multi-omics network that provides new insights into investigating the mechanistic role of gut mycobiota dysbiosis in LUAD.

PMID:41809995 | PMC:PMC12968269 | DOI:10.3389/fcimb.2026.1732958

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