J Clin Transl Hepatol. 2026 Aug 28;14(8):824-841. doi: 10.14218/JCTH.2026.00106. Epub 2026 Aug 7.

ABSTRACT

BACKGROUND AND AIMS: Despite the surging global prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) and related liver fibrosis, effective treatments remain limited. While the traditional Chinese medicine Juanyu-Xiaozhi Formula (JYXZF) is used against MASLD, its bioactive components and mechanisms are poorly understood. This study aimed to investigate the therapeutic effects of JYXZF and elucidate its underlying mechanisms of action.

METHODS: The constituents of JYXZF were characterized using ultra-high-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Its efficacy was evaluated in a rat model of metabolic dysfunction-associated steatohepatitis (MASH) induced by a high-fat/calorie diet with high-fructose/high-glucose water, utilizing serum biochemistry, histology, and glucose/insulin tolerance tests. Mechanistic validation was performed in free fatty acid-treated human hepatocellular carcinoma cell line HepG2 (HepG2) cells and HepG2/human hepatic stellate cell line LX-2 (LX-2) co-culture models using luciferase assays, chromatin immunoprecipitation-quantitative polymerase chain reaction (ChIP-qPCR), and activator protein 1 (AP-1) overexpression rescue experiments. The functional relevance of stearoyl-CoA desaturase 1 (SCD1) was further assessed in vivo through liver-targeted adeno-associated virus (AAV)-mediated Scd1 overexpression.

RESULTS: Flavonoids were identified as the main bioactive constituents. JYXZF administration alleviated metabolic dysfunction, reduced hepatic lipid accumulation, and attenuated inflammation and fibrosis in MASH rats. Multi-omics integration and machine learning-assisted target prioritization identified lipid metabolic and inflammatory pathways. Among these pathways, we selected the AP-1/peroxisome proliferator-activated receptor gamma (PPARγ)/SCD1-related lipogenic pathway for functional validation. Target perturbation experiments supported the functional involvement of AP-1 in the regulation of the PPARγ/SCD1 pathway and its contribution to the anti-steatotic effects of JYXZF.

CONCLUSIONS: JYXZF alleviates MASLD-associated steatosis and fibrosis via the AP-1/PPARγ/SCD1-related lipogenic axis, demonstrating its therapeutic potential for MASLD/MASH and providing a mechanistic basis for future clinical applications.

PMID:42723998 | PMC:PMC13558244 | DOI:10.14218/JCTH.2026.00106

J Clin Transl Hepatol. 2026 Aug 28;14(8):824-841. doi: 10.14218/JCTH.2026.00106. Epub 2026 Aug 7.

ABSTRACT

BACKGROUND AND AIMS: Despite the surging global prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) and related liver fibrosis, effective treatments remain limited. While the traditional Chinese medicine Juanyu-Xiaozhi Formula (JYXZF) is used against MASLD, its bioactive components and mechanisms are poorly understood. This study aimed to investigate the therapeutic effects of JYXZF and elucidate its underlying mechanisms of action.

METHODS: The constituents of JYXZF were characterized using ultra-high-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Its efficacy was evaluated in a rat model of metabolic dysfunction-associated steatohepatitis (MASH) induced by a high-fat/calorie diet with high-fructose/high-glucose water, utilizing serum biochemistry, histology, and glucose/insulin tolerance tests. Mechanistic validation was performed in free fatty acid-treated human hepatocellular carcinoma cell line HepG2 (HepG2) cells and HepG2/human hepatic stellate cell line LX-2 (LX-2) co-culture models using luciferase assays, chromatin immunoprecipitation-quantitative polymerase chain reaction (ChIP-qPCR), and activator protein 1 (AP-1) overexpression rescue experiments. The functional relevance of stearoyl-CoA desaturase 1 (SCD1) was further assessed in vivo through liver-targeted adeno-associated virus (AAV)-mediated Scd1 overexpression.

RESULTS: Flavonoids were identified as the main bioactive constituents. JYXZF administration alleviated metabolic dysfunction, reduced hepatic lipid accumulation, and attenuated inflammation and fibrosis in MASH rats. Multi-omics integration and machine learning-assisted target prioritization identified lipid metabolic and inflammatory pathways. Among these pathways, we selected the AP-1/peroxisome proliferator-activated receptor gamma (PPARγ)/SCD1-related lipogenic pathway for functional validation. Target perturbation experiments supported the functional involvement of AP-1 in the regulation of the PPARγ/SCD1 pathway and its contribution to the anti-steatotic effects of JYXZF.

CONCLUSIONS: JYXZF alleviates MASLD-associated steatosis and fibrosis via the AP-1/PPARγ/SCD1-related lipogenic axis, demonstrating its therapeutic potential for MASLD/MASH and providing a mechanistic basis for future clinical applications.

PMID:42723998 | PMC:PMC13558244 | DOI:10.14218/JCTH.2026.00106

Pharmacol Res. 2026 May 17:108253. doi: 10.1016/j.phrs.2026.108253. Online ahead of print.

ABSTRACT

Pancreatic ductal adenocarcinoma (PDAC) exemplifies early systemic dissemination, with circulating tumor cells (CTCs) at its core. We advance a unified conceptual framework that positions CTCs as the systemic execution hub of PDAC metastasis, dynamic entity that coordinates the metastatic cascade via four cardinal functions: Seeding, Adapting, Engineering, and Signaling. Integrating eco-evolutionary dynamics, this hub actively drives phenotypic selection, niche remodeling, and immune evasion, while providing real-time biologic intelligence through liquid biopsy. Robust clinical correlation has not yet translated into routine practice because of technical variability, biological complexity, and a lack of interventional evidence. We therefore propose an evidence-driven, phased roadmap: grounded in prospective clinical cohort data, progressing from immediate multi-center technical standardization and pragmatic trials, such as minimal residual disease (MRD)-triggered salvage therapy, to mid-term biomarker-driven adjuvant trials and long-term integration into multimodal liquid biopsy ecosystems, aimed at intercepting this execution hub. By reframing CTCs from correlative indicators to actionable therapeutic targets and dynamic sentinels, this framework charts a path toward transforming the management of this recalcitrant systemic disease.

PMID:42150733 | DOI:10.1016/j.phrs.2026.108253

Front Cell Infect Microbiol. 2026 Apr 20;16:1763765. doi: 10.3389/fcimb.2026.1763765. eCollection 2026.

ABSTRACT

BACKGROUND: Advanced gastric cancer (AGC) exhibits a high incidence in Northwest China, largely attributed to region-specific dietary patterns and environmental exposures. Its pathogenesis involves complex host-microbiota crosstalk, which has not yet been comprehensively elucidated through integrated multi-omics approaches. Herein, we employed trasncriptomic and shotgun metagenomic sequencing on paired tumoral and peritumoal mucosal tissues from 88 AGC patients in Northwest China. Our aim was to systematically characterize host gene expression profiles, the composition and functional potential of the gastric mucosal microbiota, and their intricate interrelationships.

RESULTS: Transcriptomic profiling clearly distinguished tumoral from peritumoral regions (PERMANOVA, R² = 0.24, P = 0.0001), with 8870 differentially expressed genes (DEGs) identified between the two tissue types. Tumor tissues harbored 8377 up-regulated DEG, which were enriched in extracellular matrix (ECM) organization, cell cycle regulation, signaling transduction, and inflammatory pathways (e.g., PI3K-Akt, IL-17 signaling). In contrast, peritumoral tissues showed 493 up-regulated DEGs primarily associated with metabolic processes. Host gene expression was significantly modulated by Lauren classification in tumoral mucosa (P = 0.025) and by Helicobacter pylori (Hp) infection in peritumoral tissues (P = 0.0424). Hp-infected tissues exhibited 65 up-regulated DEGs linked to transcriptional misregulation in cancer, inflammation, immune activation and mitochondrial pathways. Lauren subtypes displayed distinct transcriptomic signatures: intestinal-type AGC was enriched in metabolic processes, diffuse-type in immune and signal transduction pathways, and mixed-type in Ras/MAPK/ErbB and NF-κB signaling pathways. Correlation analysis between the 8870 DEGs and seven differentially abundant bacterial species (e.g., Serratia surfactantfaciens, Pseudomonas protegens, Prevotella jejuni, and Streptococcus infantis) revealed 13199 significant correlations. Among these, S. surfactantfaciens and P. protegens exhibited the strongest connectivity with host genes. Functionally, the correlated DEGs were involved in ECM structure, cell cycle progression, immune and inflammatory responses, cellular proliferation and differentiation, and metabolic processes.

CONCLUSIONS: Our findings demonstrated phenotype- and tissue-specific regulation of host gene expression in AGC and revealed extensive host-microbe interactions. This work fills a critical gap in multi-omics research on AGC in the Northwest Chinese population and suggests potential diagnostic and therapeutic targets for AGC.

PMID:42088021 | PMC:PMC13136179 | DOI:10.3389/fcimb.2026.1763765

Naunyn Schmiedebergs Arch Pharmacol. 2026 Apr 5. doi: 10.1007/s00210-026-05251-7. Online ahead of print.

ABSTRACT

Lung adenocarcinoma (LUAD) is one of the leading causes of cancer-related deaths worldwide, and its complex tumor microenvironment (TME) is a key barrier to treatment. PANoptosis is a novel programmed cell death mechanism that integrates features of pyroptosis, apoptosis, and necroptosis. However, its core regulatory network and cell specific role in LUAD are still unclear. This study integrated three LUAD transcriptome datasets, screened differentially expressed genes through bioinformatics analysis, and intersected with PANoptosis-related genes to construct a protein interaction network, using a combination of 113 machine learning algorithms to screen and validate core genes and using CIBERSORT and single-cell transcriptome data to analyze the spatial expression characteristics of immune cell infiltration and core genes. Finally, the intervention mechanism of core targets and ginsenosides was validated through molecular docking, immunohistochemistry, and cell experiments (CCK-8, Western Blot). Six core genes of LUAD PANoptosis, including IRF1, NLRP3, CASP1, TIMP1, S100A8, and TLR4, were identified in the study. Single-cell analysis revealed that these genes were significantly enriched in M2 macrophages. Functional enrichment indicates that they jointly regulate death- and inflammation-related pathways such as NF-κB signaling and NOD-like receptor signaling. In vitro experiments have confirmed that ginsenosides can induce PANoptosis, promote tumor cell death, or inhibit LUAD cell proliferation by upregulating the ZBP1/AIM2/RIPK3/CASP1 death complex and inhibiting the TLR4/NLRP3 survival signaling axis. This study systematically revealed a PANoptosis core gene network centered on M2 macrophages in LUAD, elucidating a new mechanism by which ginsenosides induce integrated cell death by regulating this network. This provides new potential targets and theoretical basis for the immunotherapy of LUAD and the development of traditional Chinese medicine monomers.

PMID:41935997 | DOI:10.1007/s00210-026-05251-7

Naunyn Schmiedebergs Arch Pharmacol. 2026 Apr 5. doi: 10.1007/s00210-026-05251-7. Online ahead of print.

ABSTRACT

Lung adenocarcinoma (LUAD) is one of the leading causes of cancer-related deaths worldwide, and its complex tumor microenvironment (TME) is a key barrier to treatment. PANoptosis is a novel programmed cell death mechanism that integrates features of pyroptosis, apoptosis, and necroptosis. However, its core regulatory network and cell specific role in LUAD are still unclear. This study integrated three LUAD transcriptome datasets, screened differentially expressed genes through bioinformatics analysis, and intersected with PANoptosis-related genes to construct a protein interaction network, using a combination of 113 machine learning algorithms to screen and validate core genes and using CIBERSORT and single-cell transcriptome data to analyze the spatial expression characteristics of immune cell infiltration and core genes. Finally, the intervention mechanism of core targets and ginsenosides was validated through molecular docking, immunohistochemistry, and cell experiments (CCK-8, Western Blot). Six core genes of LUAD PANoptosis, including IRF1, NLRP3, CASP1, TIMP1, S100A8, and TLR4, were identified in the study. Single-cell analysis revealed that these genes were significantly enriched in M2 macrophages. Functional enrichment indicates that they jointly regulate death- and inflammation-related pathways such as NF-κB signaling and NOD-like receptor signaling. In vitro experiments have confirmed that ginsenosides can induce PANoptosis, promote tumor cell death, or inhibit LUAD cell proliferation by upregulating the ZBP1/AIM2/RIPK3/CASP1 death complex and inhibiting the TLR4/NLRP3 survival signaling axis. This study systematically revealed a PANoptosis core gene network centered on M2 macrophages in LUAD, elucidating a new mechanism by which ginsenosides induce integrated cell death by regulating this network. This provides new potential targets and theoretical basis for the immunotherapy of LUAD and the development of traditional Chinese medicine monomers.

PMID:41935997 | DOI:10.1007/s00210-026-05251-7