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