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

Pharmacol Res. 2026 Apr 9:108186. doi: 10.1016/j.phrs.2026.108186. Online ahead of print.

ABSTRACT

Community-acquired pneumonia (CAP) remains a major global public health challenge with substantial morbidity and mortality. Although preclinical studies suggest that Maxing Huoqiao (MXHQ) granule may have therapeutic potential for pneumonia, high-quality clinical evidence is still limited. We conducted a multicenter, double-blind, randomized, placebo-controlled trial at two tertiary hospitals in China to evaluate the clinical efficacy of MXHQ as adjunctive therapy and to explore its potential mechanisms in adults with nonsevere CAP receiving standard moxifloxacin treatment. A total of 96 patients were enrolled and randomized (1:1:1) to receive standard-dose MXHQ, low-dose MXHQ, or placebo in addition to moxifloxacin for 7 days, with a 14-day follow-up. The primary endpoint was clinical cure, defined as composite recovery of major respiratory symptoms, lung rales, and fever; secondary endpoints included symptom relief, radiographic improvement, and safety. Compared with placebo, standard-dose MXHQ was associated with a higher day-14 clinical cure rate (30.78% vs. 68.97%; RR = 0.45, 95% CI = 0.24-0.83; P < 0.01). Furthermore, the standard-dose intervention was correlated with a shorter time to relief and recovery of cough and sputum (P < 0.05), as well as improvements in symptom scores (P < 0.05) and promoting lesion absorption on chest CT (P < 0.05). Low-dose MXHQ showed no significant clinical benefit, whereas safety profiles were comparable across all groups. Transcriptomic analyses of peripheral blood mononuclear cells, complemented by a Streptococcus pneumonia animal model, indicated that the clinical benefits of MXHQ are linked to the modulation of inflammation and innate immunity. These omics and in vivo observations suggest a potential mechanism underlying the protective effects of MXHQ against inflammatory injury and promotion of tissue repair, involving the regulation of anti-inflammatory mediators and tissue repair-related factors. (Chictr.org.cn, ID Number: ChiCTR2400082095).

PMID:41966499 | DOI:10.1016/j.phrs.2026.108186

Gene. 2026 Apr 9:150160. doi: 10.1016/j.gene.2026.150160. Online ahead of print.

ABSTRACT

Porcine gastric epithelial cells (PGECs) serve as a valuable model for studying the molecular and pathogenic mechanisms of the stomach. However, PGECs face limitations such as isolation challenges, short lifespan, and restricted proliferation. To address this, we established an immortalized PGECs (i-PGECs) to enable in vitro investigation of pathogen infection mechanisms. Primary PGECs were isolated from the acid-secreting glands using stepwise digestion with multiple enzymes (dispase II/collagenase I/hyaluronidase). Immortalization was achieved via lentiviral vectors expressing simian virus 40 large T antigen (SV40T) and human telomerase reverse transcriptase (hTERT), with successful expression confirmed by qRT-PCR (P < 0.05). Epithelial identity of i-PGECs was confirmed by stable expression of CK18, EpCAM, and E-cadherin, as shown by qRT-PCR and immunofluorescence. i-PGECs retained the morphological and ultrastructural features of PGECs and exhibited enhanced proliferation, as demonstrated by WST-8 assays, apoptosis and cell cycle analysis, karyotyping, and transmission electron microscopy (TEM). Telomere length analysis and scratch wound assays demonstrated stable telomere maintenance and consistent migration capacity unaffected by passaging. RNA-sequencing and differential expressed genes (DEGs) analysis revealed significantly upregulating of genes involved in cell proliferation pathways (P < 0.01). Following aflatoxin B1 (AFB1) exposure, i-PGECs significantly upregulated immune-related factors, such as NPC1 and PLAUR (P < 0.01). CRISPR/Cas9-mediated knockout of NPC1 in i-PGECs conferred increased resistance to AFB1-induced cytotoxicity, as shown by WST-8 assay. The i-PGECs remained stable after more than 50 passages, supporting their use as a reliable for in vitro model investigating the mechanisms of toxicity infection in the porcine gastric epithelium.

PMID:41966285 | DOI:10.1016/j.gene.2026.150160

Mol Divers. 2026 Apr 12. doi: 10.1007/s11030-026-11545-y. Online ahead of print.

NO ABSTRACT

PMID:41966666 | DOI:10.1007/s11030-026-11545-y

Commun Biol. 2026 Apr 11. doi: 10.1038/s42003-026-10033-1. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a complex disease without clear etiology or effective therapy. While DNA methylation has been implicated in IPF pathogenesis, the tissue-specific causal effects of the epigenetic factors on IPF remain undetermined. Here, we perform epigenome-wide Mendelian randomization using blood-based methylation quantitative trait loci of 420,509 CpG sites and genome-wide association study for IPF to elucidate the causal effects of the CpG sites on IPF. Totally, 452 CpG sites has shown putative causal effects on IPF risk after Bonferroni correction. Among them, 13 CpG sites have shown strong colocalization evidence with genetic factors associated with IPF. Specifically, DNA methylation at CpG sites within MAN2A2 and TRIM27 shows significant differences between IPF lungs and controls, correlating with altered mRNA expressions of these genes in lung tissues. The CpG site in MAN2A2 is a binding site of ZNF384 according to transcription factor databases. RNA sequencing in the TGFβ1-induced alveolar epithelia confirms significantly reduced expression of MAN2A2 and ZNF384 comparing to the controls. Collectively, our study suggests a putative causal link between DNA methylation within MAN2A2 and IPF risk, wherein lung-specific DNA methylation in MAN2A2 may perturb the interaction between ZNF384 and MAN2A2, revealing novel roles for these genes in IPF pathogenesis.

PMID:41965819 | DOI:10.1038/s42003-026-10033-1

Commun Biol. 2026 Apr 11. doi: 10.1038/s42003-026-10033-1. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a complex disease without clear etiology or effective therapy. While DNA methylation has been implicated in IPF pathogenesis, the tissue-specific causal effects of the epigenetic factors on IPF remain undetermined. Here, we perform epigenome-wide Mendelian randomization using blood-based methylation quantitative trait loci of 420,509 CpG sites and genome-wide association study for IPF to elucidate the causal effects of the CpG sites on IPF. Totally, 452 CpG sites has shown putative causal effects on IPF risk after Bonferroni correction. Among them, 13 CpG sites have shown strong colocalization evidence with genetic factors associated with IPF. Specifically, DNA methylation at CpG sites within MAN2A2 and TRIM27 shows significant differences between IPF lungs and controls, correlating with altered mRNA expressions of these genes in lung tissues. The CpG site in MAN2A2 is a binding site of ZNF384 according to transcription factor databases. RNA sequencing in the TGFβ1-induced alveolar epithelia confirms significantly reduced expression of MAN2A2 and ZNF384 comparing to the controls. Collectively, our study suggests a putative causal link between DNA methylation within MAN2A2 and IPF risk, wherein lung-specific DNA methylation in MAN2A2 may perturb the interaction between ZNF384 and MAN2A2, revealing novel roles for these genes in IPF pathogenesis.

PMID:41965819 | DOI:10.1038/s42003-026-10033-1

Discov Oncol. 2026 Apr 11. doi: 10.1007/s12672-026-04951-z. Online ahead of print.

ABSTRACT

BACKGROUND: Hepatocellular carcinoma (HCC) is a major cause of cancer-related mortality. Chromosome 8 open reading frame 33 (C8orf33) has been noted as a potential oncogenic factor in several cancers, but its biological roles and regulatory mechanism in HCC microenvironment remain unknown.

METHODS: We integrated bulk RNA sequencing, single-cell RNA sequencing (scRNA-seq), and spatial transcriptomics (ST) to characterize the expression landscape of C8orf33. We then performed C8orf33 loss-of-function studies in HCC cell lines, including in vitro phenotypic assays and subcutaneous xenografts.

RESULTS: C8orf33 was broadly overexpressed and associated with unfavorable prognosis across multiple Cancers. In HCC, higher C8orf33 aligned with advanced stage and shorter overall survival. C8orf33 knockdown reduced proliferation and migration, impaired tumorigenic capacity, and increased apoptosis. ScRNA-seq analyses identified a malignant population of Epi3 with high C8orf33 expression. Cell-cell communication analysis suggested that C8orf33-high Epi3 state was associated with an enriched MIF-CD74/CXCR4/CD44 signaling program toward macrophage populations with M2-like features. ST analyses further confirmed the colocalization of C8orf33 with malignant features in tumor cores. In Huh7 cells, C8orf33 knockdown was accompanied by reduced mRNA and protein levels of MIF and its receptor components. Consistently, xenografts derived from C8orf33-silenced cells showed lower expression of these MIF-axis components and reduced infiltration of CD163 and CD206-positive macrophages.

CONCLUSION: These results support a tumor-promoting association of C8orf33 in HCC and suggest a potential link to macrophage-associated immunomodulatory features, nominating C8orf33 as a candidate biomarker and therapeutic target.

PMID:41965457 | DOI:10.1007/s12672-026-04951-z

Discov Oncol. 2026 Apr 11. doi: 10.1007/s12672-026-04951-z. Online ahead of print.

ABSTRACT

BACKGROUND: Hepatocellular carcinoma (HCC) is a major cause of cancer-related mortality. Chromosome 8 open reading frame 33 (C8orf33) has been noted as a potential oncogenic factor in several cancers, but its biological roles and regulatory mechanism in HCC microenvironment remain unknown.

METHODS: We integrated bulk RNA sequencing, single-cell RNA sequencing (scRNA-seq), and spatial transcriptomics (ST) to characterize the expression landscape of C8orf33. We then performed C8orf33 loss-of-function studies in HCC cell lines, including in vitro phenotypic assays and subcutaneous xenografts.

RESULTS: C8orf33 was broadly overexpressed and associated with unfavorable prognosis across multiple Cancers. In HCC, higher C8orf33 aligned with advanced stage and shorter overall survival. C8orf33 knockdown reduced proliferation and migration, impaired tumorigenic capacity, and increased apoptosis. ScRNA-seq analyses identified a malignant population of Epi3 with high C8orf33 expression. Cell-cell communication analysis suggested that C8orf33-high Epi3 state was associated with an enriched MIF-CD74/CXCR4/CD44 signaling program toward macrophage populations with M2-like features. ST analyses further confirmed the colocalization of C8orf33 with malignant features in tumor cores. In Huh7 cells, C8orf33 knockdown was accompanied by reduced mRNA and protein levels of MIF and its receptor components. Consistently, xenografts derived from C8orf33-silenced cells showed lower expression of these MIF-axis components and reduced infiltration of CD163 and CD206-positive macrophages.

CONCLUSION: These results support a tumor-promoting association of C8orf33 in HCC and suggest a potential link to macrophage-associated immunomodulatory features, nominating C8orf33 as a candidate biomarker and therapeutic target.

PMID:41965457 | DOI:10.1007/s12672-026-04951-z