Cell Rep Med. 2026 Apr 10:102741. doi: 10.1016/j.xcrm.2026.102741. Online ahead of print.

ABSTRACT

Combined small-cell lung cancer (cSCLC) is an aggressive subtype of SCLC with mixed histologic components. Despite heterogeneity and poorer prognosis than de novo SCLC, cSCLC is managed as SCLC because molecular insight into biology, lineage plasticity, and tumor microenvironment (TME) is limited. We perform spatial whole-exome sequencing, spatial transcriptomics, and single-nucleus RNA sequencing across 19 treatment-naive cSCLC tumors. Different histologic components share a monoclonal origin, whereas divergence associates with distinct mutation and copy-number alteration patterns. Our results define spatially exclusive or interspersed tumor domains with distinct TME and immune landscapes; fibroblast-rich boundaries enriched for an aggressive fibroblast subtype may shape TME and treatment responses. We identify lineage plasticity, including adenocarcinoma-to-SCLC transdifferentiation and SCLC-subtype coexistence, and develop cSCLC Detector, a sensitive mutation-based assay improving cSCLC detection in tissue and liquid biopsies. These findings illuminate cSCLC evolution and heterogeneity, underscoring the need for tailored diagnostic and therapeutic strategies for this aggressive subtype.

PMID:41966692 | DOI:10.1016/j.xcrm.2026.102741

Cell Rep Med. 2026 Apr 10:102741. doi: 10.1016/j.xcrm.2026.102741. Online ahead of print.

ABSTRACT

Combined small-cell lung cancer (cSCLC) is an aggressive subtype of SCLC with mixed histologic components. Despite heterogeneity and poorer prognosis than de novo SCLC, cSCLC is managed as SCLC because molecular insight into biology, lineage plasticity, and tumor microenvironment (TME) is limited. We perform spatial whole-exome sequencing, spatial transcriptomics, and single-nucleus RNA sequencing across 19 treatment-naive cSCLC tumors. Different histologic components share a monoclonal origin, whereas divergence associates with distinct mutation and copy-number alteration patterns. Our results define spatially exclusive or interspersed tumor domains with distinct TME and immune landscapes; fibroblast-rich boundaries enriched for an aggressive fibroblast subtype may shape TME and treatment responses. We identify lineage plasticity, including adenocarcinoma-to-SCLC transdifferentiation and SCLC-subtype coexistence, and develop cSCLC Detector, a sensitive mutation-based assay improving cSCLC detection in tissue and liquid biopsies. These findings illuminate cSCLC evolution and heterogeneity, underscoring the need for tailored diagnostic and therapeutic strategies for this aggressive subtype.

PMID:41966692 | DOI:10.1016/j.xcrm.2026.102741

Phytomedicine. 2026 Mar 30;155:158128. doi: 10.1016/j.phymed.2026.158128. Online ahead of print.

ABSTRACT

BACKGROUND: The global prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) continues to rise, and its pathogenesis is complex, creating an urgent need to discover novel and effective therapeutic strategies. The Zuogui Jiangtang Qinggan formula (ZGJTQGF), an approved in-hospital preparation, has demonstrated significant clinical efficacy in treating diabetes over several decades. However, the mechanisms underlying its potential therapeutic effects on MASLD remain unclear PURPOSE: This study systematically investigates the therapeutic effects and molecular mechanisms of ZGJTQGF on MASLD through the integration of network pharmacology and multi-omics strategies.

METHODS: The model of MASLD was successfully induced in db/db mice by a high-fat diet (HFD), which displayed characteristic dyslipidaemia. Serum biomarkers, histology, and hepatic multi-omics analyses were employed to assess metabolic status, steatosis, targets, and pathways. Ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS), molecular docking analysis and in vitro verification were applied to explore the active ingredients of ZGJTQGF.

RESULTS: ZGJTQGF significantly reduced dyslipidemia in HFD-fed mice, inhibited pro-inflammatory cytokines, and restored glucose metabolic balance by lowering levels of glucose, insulin, OGTT, and HOMA-IR. Histopathology showed reduced lipid deposition and hepatocyte damage. Comprehensive multi-omics analysis suggested that regulating the AMPK/PGC-1α/PPARα and FXR-BSEP signaling pathways could be potential targets for ZGJTQGF in reprogramming glucose and lipid metabolism in MASLD treatment. Blood component analysis identified 52 ZGJTQGF-derived compounds. In molecular docking experiments, Wogonin, Naringenin, Quercetin, Tanshinone IIA and Berberine showed high-affinity binding to core targets in AMPK, PPARα, PGC-1α, FXR and FAS. Mechanistically, ZGJTQGF activated AMPK/PPARα /PGC-1α and FXR-BSEP signaling pathway, promotes fatty acid β oxidation and enhances energy consumption in AML-2 and 3T3-L1 cells, downregulates SREBP-1-dependent adipogenesis (reduces ACC1 and FAS expression), alleviates MASLD driven reprogramming of glucose and lipid metabolism, and regulates lipid metabolism and fatty acid synthesis.

CONCLUSIONS: ZGJTQGF activates the AMPK/PPARα /PGC-1α pathway and inhibits abnormal lipid accumulation in diabetic fatty liver by promoting fatty acid β-oxidation, energy consumption, and bile acid metabolism. These findings provide new insights into the mechanism of ZGJTQGF in the treatment of diabetic fatty liver disease.

PMID:41962267 | DOI:10.1016/j.phymed.2026.158128

Phytomedicine. 2026 Mar 30;155:158128. doi: 10.1016/j.phymed.2026.158128. Online ahead of print.

ABSTRACT

BACKGROUND: The global prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) continues to rise, and its pathogenesis is complex, creating an urgent need to discover novel and effective therapeutic strategies. The Zuogui Jiangtang Qinggan formula (ZGJTQGF), an approved in-hospital preparation, has demonstrated significant clinical efficacy in treating diabetes over several decades. However, the mechanisms underlying its potential therapeutic effects on MASLD remain unclear PURPOSE: This study systematically investigates the therapeutic effects and molecular mechanisms of ZGJTQGF on MASLD through the integration of network pharmacology and multi-omics strategies.

METHODS: The model of MASLD was successfully induced in db/db mice by a high-fat diet (HFD), which displayed characteristic dyslipidaemia. Serum biomarkers, histology, and hepatic multi-omics analyses were employed to assess metabolic status, steatosis, targets, and pathways. Ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS), molecular docking analysis and in vitro verification were applied to explore the active ingredients of ZGJTQGF.

RESULTS: ZGJTQGF significantly reduced dyslipidemia in HFD-fed mice, inhibited pro-inflammatory cytokines, and restored glucose metabolic balance by lowering levels of glucose, insulin, OGTT, and HOMA-IR. Histopathology showed reduced lipid deposition and hepatocyte damage. Comprehensive multi-omics analysis suggested that regulating the AMPK/PGC-1α/PPARα and FXR-BSEP signaling pathways could be potential targets for ZGJTQGF in reprogramming glucose and lipid metabolism in MASLD treatment. Blood component analysis identified 52 ZGJTQGF-derived compounds. In molecular docking experiments, Wogonin, Naringenin, Quercetin, Tanshinone IIA and Berberine showed high-affinity binding to core targets in AMPK, PPARα, PGC-1α, FXR and FAS. Mechanistically, ZGJTQGF activated AMPK/PPARα /PGC-1α and FXR-BSEP signaling pathway, promotes fatty acid β oxidation and enhances energy consumption in AML-2 and 3T3-L1 cells, downregulates SREBP-1-dependent adipogenesis (reduces ACC1 and FAS expression), alleviates MASLD driven reprogramming of glucose and lipid metabolism, and regulates lipid metabolism and fatty acid synthesis.

CONCLUSIONS: ZGJTQGF activates the AMPK/PPARα /PGC-1α pathway and inhibits abnormal lipid accumulation in diabetic fatty liver by promoting fatty acid β-oxidation, energy consumption, and bile acid metabolism. These findings provide new insights into the mechanism of ZGJTQGF in the treatment of diabetic fatty liver disease.

PMID:41962267 | DOI:10.1016/j.phymed.2026.158128

World J Surg Oncol. 2026 Apr 7. doi: 10.1186/s12957-026-04321-7. Online ahead of print.

NO ABSTRACT

PMID:41947143 | DOI:10.1186/s12957-026-04321-7

J Ethnopharmacol. 2026 Apr 6:121628. doi: 10.1016/j.jep.2026.121628. Online ahead of print.

ABSTRACT

ETHNOPHARMACOLOGICAL RELEVANCE: Chuanminshen violaceum Sheh et Shan is a medicinal-and-edible Apiaceae plant in China recorded for yin nourishment, lung/spleen tonification, and phlegm resolution, and used for cough and chronic respiratory complaints.

STUDY AIM: To synthesize current evidence on botanical resources, chemistry, pharmacology, and applications of C. violaceum, and to define priorities for standardized and safe development.

MATERIALS AND METHODS: This review integrates studies on resource distribution and ecological adaptability, multi-fraction phytochemistry, extraction-purification and formulation technologies, preclinical pharmacology, and quality, safety, and regulatory considerations.

RESULTS: C. violaceum contains structurally diverse polysaccharides plus volatile oils (often polyacetylene-rich), phenolics (e.g., chlorogenic acid and rutin), PUFA-rich lipids, and newly reported minor constituents. Polysaccharides show variable monosaccharide profiles, molecular-weight ranges, and linkage/branching patterns, strongly influenced by extraction-purification; derivatization (e.g., sulfation/selenization) and delivery systems can further tune physicochemical properties. Preclinical studies report antioxidant, anti-inflammatory, immunomodulatory, cardioprotective, and antiviral effects, commonly linked to Nrf2/Keap1 redox defense, inflammatory signaling control, TLR2/4-related immune regulation, gut-barrier reinforcement with microbiota remodeling, and anti-ferroptotic protection in myocardial ischemia-reperfusion models. Applications span traditional dosage forms and functional foods, but translation is limited by origin/process variability, incomplete long-term safety and ADME data, and regulatory uncertainty.

CONCLUSIONS: C. violaceum is a promising ethnomedicinal resource with clear part-specific features and polysaccharide-centered potential. Future work should combine multi-omics with target validation, fingerprint-guided QC and traceability, greener scalable processing, and regulatory-aligned safety packages to enable reproducible products.

PMID:41951195 | DOI:10.1016/j.jep.2026.121628

JHEP Rep. 2026 Feb 18;8(5):101790. doi: 10.1016/j.jhepr.2026.101790. Online ahead of print.

ABSTRACT

BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) exhibits diverse aetiologies and molecular heterogeneity, with a median 5-year overall survival of <70% due to high recurrence rates following curative-intent surgery. This study investigated the complex tumour microenvironment (TME) in HCC and explored interactions between various cell types and their roles in disease recurrence.

METHODS: Using a multi-omics approach on multi-region samples of surgically resected HCC from the PLANet 1.0 cohort (NCT03267641), we performed spatial transcriptomics on 17 tissue samples from four patients and bulk RNA sequencing on 329 sectors from 90 patients. Findings were validated using immunofluorescence and multiplex immunohistochemistry.

RESULTS: Our analysis revealed extensive intra- and intertumour gene expression heterogeneity and identified a specific subset of endothelial cells (ECs), INTS6⁺ ECs, enriched and spatially colocalised with tumour cells in primary tumours from patients with recurrence (p = 0.021, n = 49). A significant ANGPTL4-SDC1 ligand-receptor interaction was identified between INTS6⁺ ECs and tumour cells. Notably, INTS6⁺ ECs were enriched in microvascular invasion regions and spatially colocalised with tumour cells in patients with recurrence (p = 0.036, n = 53). These findings highlight endothelial-tumour cell interactions within the TME as potential therapeutic targets.

CONCLUSIONS: INTS6⁺ ECs are enriched in microvascular invasion regions and spatially colocalised with tumour cells in recurrent HCC, suggesting a potential role in disease recurrence and representing a promising therapeutic target within the TME.

IMPACT AND IMPLICATIONS: The spatial co-localisation of cell types plays a significant role in the recurrence of hepatocellular carcinoma. In this study, we have pinpointed a particular group of endothelial cells, known as INTS6+ endothelial cells, which are spatially colocalised with tumour cells and enriched in microvascular invasion regions in patients experiencing recurrence. These discoveries highlight novel therapeutic targets that focus on endothelial cell interactions within the tumour microenvironment to prevent recurrence and enhance overall patient survival.

PMID:41950768 | DOI:10.1016/j.jhepr.2026.101790

JHEP Rep. 2026 Feb 18;8(5):101790. doi: 10.1016/j.jhepr.2026.101790. Online ahead of print.

ABSTRACT

BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) exhibits diverse aetiologies and molecular heterogeneity, with a median 5-year overall survival of <70% due to high recurrence rates following curative-intent surgery. This study investigated the complex tumour microenvironment (TME) in HCC and explored interactions between various cell types and their roles in disease recurrence.

METHODS: Using a multi-omics approach on multi-region samples of surgically resected HCC from the PLANet 1.0 cohort (NCT03267641), we performed spatial transcriptomics on 17 tissue samples from four patients and bulk RNA sequencing on 329 sectors from 90 patients. Findings were validated using immunofluorescence and multiplex immunohistochemistry.

RESULTS: Our analysis revealed extensive intra- and intertumour gene expression heterogeneity and identified a specific subset of endothelial cells (ECs), INTS6⁺ ECs, enriched and spatially colocalised with tumour cells in primary tumours from patients with recurrence (p = 0.021, n = 49). A significant ANGPTL4-SDC1 ligand-receptor interaction was identified between INTS6⁺ ECs and tumour cells. Notably, INTS6⁺ ECs were enriched in microvascular invasion regions and spatially colocalised with tumour cells in patients with recurrence (p = 0.036, n = 53). These findings highlight endothelial-tumour cell interactions within the TME as potential therapeutic targets.

CONCLUSIONS: INTS6⁺ ECs are enriched in microvascular invasion regions and spatially colocalised with tumour cells in recurrent HCC, suggesting a potential role in disease recurrence and representing a promising therapeutic target within the TME.

IMPACT AND IMPLICATIONS: The spatial co-localisation of cell types plays a significant role in the recurrence of hepatocellular carcinoma. In this study, we have pinpointed a particular group of endothelial cells, known as INTS6+ endothelial cells, which are spatially colocalised with tumour cells and enriched in microvascular invasion regions in patients experiencing recurrence. These discoveries highlight novel therapeutic targets that focus on endothelial cell interactions within the tumour microenvironment to prevent recurrence and enhance overall patient survival.

PMID:41950768 | DOI:10.1016/j.jhepr.2026.101790

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; Mif^flox/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