Adv Sci (Weinh). 2026 Apr 3:e17640. doi: 10.1002/advs.202517640. Online ahead of print.

ABSTRACT

The embryonic coelomic mesothelium acts as a critical progenitor hub during mammalian organogenesis, undergoing epithelial-to-mesenchymal transition (EMT) to drive vascular growth and parenchymal development in visceral organs. A prominent example is the epicardium, which plays an essential role during heart development. The principles of gene regulation in the coelomic mesothelium remain poorly defined. Specifically, it is unclear how cis-regulatory elements, including enhancers, orchestrate the spatiotemporal patterns of gene expression required for mesothelial identity and function. Here, a multi-omic approach was used to identify trans- and cis-regulatory elements that regulate mesothelial gene expression in three organs: heart, lung, and pancreas. This analysis uncovers a cardiac-specific regulatory circuit in which the transcription factor (TF) TBX20 selectively activates epicardial enhancers to orchestrate essential developmental programs. In contrast, TF MAF orchestrates pan-mesothelial gene expression via conserved CREs, which are absent in non-mesothelial lineages. Our integrated genomic analysis reveals MAF as a central custodian of mesothelial identity, a role underscored by its negative correlation with EMT, evolutionary conservation, and dynamic regulatory activity throughout development. Our work establishes a foundational blueprint of the gene regulatory landscape governing the coelomic mesothelium, defining both conserved principles and organ-specific mechanisms of spatiotemporal gene expression during early mammalian development.

PMID:41933934 | DOI:10.1002/advs.202517640

Future Sci OA. 2026 Dec;12(1):2653101. doi: 10.1080/20565623.2026.2653101. Epub 2026 Apr 3.

ABSTRACT

BACKGROUND: Clarification of the molecular mechanism of malignant tumor progression, identification of the key signaling pathways and molecules involved in the processes of invasion and metastasis, and identification of new targets and strategies for effective tumor treatment are extremely important for scientific research and clinical application prospects.

METHODS: Based on large-sample data mining, we first evaluated the expression and mutation profiles of SPRR family genes across cancers and then focused on the molecular functions of SPRR2D across cancers.

RESULTS: Multi-omics experiments revealed that SPRR2D is significantly overexpressed in various tumors, especially in LUSC. ROC curve analysis revealed that SPRR2D demonstrated significant diagnostic efficacy across cancers. Cox regression analysis revealed that the expression of SPRR2D was associated with the survival time of patients with various tumors. Moreover, the expression of SPRR2D is closely related to tumor immune infiltration. GDSC data analysis revealed that the expression levels of SPRR1A, SPRR1B, SPRR2A, SPRR3, and SPRR2D are negatively correlated with the sensitivity to gefitinib, trametinib, bosutinib, afatinib, lapatinib, and erlotinib.

CONCLUSIONS: From a multi-omics perspective, it was revealed that SPRR2D plays a significant role in regulating tumorigenesis and drug sensitivity in tumors.

PMID:41933926 | PMC:PMC13051589 | DOI:10.1080/20565623.2026.2653101

Gastroenterology. 2026 Apr 1:S0016-5085(26)00312-4. doi: 10.1053/j.gastro.2026.03.020. Online ahead of print.

ABSTRACT

The burden of chronic liver disease is rapidly increasing worldwide, driven primarily by metabolic dysfunction-associated steatotic liver disease (MASLD), metabolic and alcohol-associated liver disease (MetALD), and alcohol-associated liver disease (ALD). Genetic predisposition contributes substantially to variability in disease onset, progression, and outcomes, and recent advances in genomic discovery have brought polygenic risk scores (PRS) and targeted sequencing closer to clinical relevance. This review summarizes the role of genetic testing in clinical hepatology, including monogenic drivers of disease and the growing role of common variants and PRS. Specific populations, including cryptogenic cirrhosis and lean MASLD patients, may be enriched for monogenic drivers of disease. In addition, patients with chronic liver disease may benefit from incorporation of genetic risk scores including PNPLA3, TM6SF2, HSD17B13, and other key variants in determining risk for fibrosis progression and cirrhosis. Across MASLD and ALD, PRS demonstrate modest improvements in predicting fibrosis progression and liver-related events, especially when integrated with clinical risk factors and comorbidities. However, their performance remains limited for population-level screening. Similarly, PRS alone has limited diagnostic accuracy for hepatocellular carcinoma and more complex models with clinical features and multi-omic biomarkers are likely needed. Emerging therapies targeting PNPLA3 and HSD17B13 variants represent a paradigm shift toward genetically informed treatment. Yet challenges remain, including limited ancestral diversity in genomic datasets, pleiotropic effects of variants, cost-effectiveness, and the need for integration with other omics and electronic medical records. As evidence matures, combining genetic risk with clinical and environmental factors may enable more personalized approaches to prognostication and therapy in liver disease.

PMID:41932449 | DOI:10.1053/j.gastro.2026.03.020

Am J Hum Genet. 2026 Apr 2;113(4):828-841. doi: 10.1016/j.ajhg.2026.03.008.

ABSTRACT

Reliable reference transcriptome prediction models are key to accurate multi-ancestry transcriptome-wide association studies (TWASs). We propose three methods leveraging functionally informed variants (FIVs) for transcriptome prediction models to improve multi-ancestry TWASs. We trained models on 1,287 multi-ancestry participants from the Trans-Omics for Precision Medicine (TOPMed) program Multi-Ethnic Study of Atherosclerosis (MESA) with RNA sequencing (RNA-seq) data from peripheral blood mononuclear cells (PBMCs). We validated models' prediction accuracy on two external independent datasets, Geuvadis and Jackson Heart Study. To test robustness of our methods for TWASs, we integrated models with three multi-ancestry GWASs from blood cell, lipid, and pulmonary function traits, respectively. Our methods presented similar prediction accuracy while using a smaller and functionally informed set of variants compared to the benchmark method, elastic net (EN). Overall, our methods achieved higher power and accuracy (with average improved accuracy of 24% over EN) for TWASs. However, no single proposed method outperformed all GWAS traits. To further improve TWAS performance, we propose an omnibus approach that aggregates TWAS summary statistics from our methods. The omnibus approach yielded the highest number of Bonferroni-significant TWAS genes for all GWAS traits, and it further improved TWAS power and accuracy for blood cell traits. Additionally, the omnibus approach detected some trait-relevant important genes that the EN missed. Our study demonstrates the value of including FIVs in multi-ancestry transcriptome prediction models for improving TWAS performance. Further, the observed TWAS improvement depends on the GWAS trait's relevance to the PBMCs used to build our transcriptome prediction models.

PMID:41932314 | DOI:10.1016/j.ajhg.2026.03.008

Phytomedicine. 2026 Mar 27;155:158126. doi: 10.1016/j.phymed.2026.158126. Online ahead of print.

ABSTRACT

BACKGROUND: Mitochondrial damage can induce the release of mitochondrial DNA (mtDNA), leading to oxidative stress and activation of immune responses. Targeting mitochondrial dysfunction may thus represent a therapeutic strategy for gastric cancer. Isobavachalcone (IBC), a prenylated chalcone derived from Psoralea corylifolia L., has demonstrated antitumor activity, but its mechanism of action remains unclear, limiting its clinical application.

PURPOSE: This study aimed to investigate the antitumor effects of IBC in gastric cancer and to elucidate the underlying molecular mechanisms, with a focus on mitochondrial damage and immune activation.

STUDY DESIGN: The study combined in vitro and in vivo assays with multi-omics sequencing and network pharmacology to identify IBC's therapeutic target and downstream signaling pathways.

METHODS: Gastric cancer cells and mouse models were treated with IBC to assess its inhibitory effects. Multi-omics approaches and network pharmacology were used to identify potential targets. ROS production, mitochondrial membrane integrity, and immune pathway activation were evaluated via biochemical and molecular assays.

RESULTS: IBC significantly suppresses gastric cancer growth both in vitro and in vivo. Integrated analysis identifies dihydroorotate dehydrogenase (DHODH) as a direct target of IBC. DHODH deficiency can induce mitochondrial membrane remodeling and STING pathway activation. Inhibition of DHODH by IBC induces ROS accumulation, mitochondrial membrane remodeling, and activation of the STING pathway, promoting antitumor immune responses. This study demonstrates that IBC enhances antitumor immunity in gastric cancer through mitochondrial damage-mediated mechanisms.

CONCLUSION: IBC exerts dual antitumor and immunostimulatory effects in gastric cancer by targeting DHODH, inducing mitochondrial damage, and activating the STING pathway, highlighting its promising therapeutic potential in gastric cancer.

PMID:41931998 | DOI:10.1016/j.phymed.2026.158126