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

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