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

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

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

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