Betaine‐homocysteine methyltransferase attenuates liver ischemia–reperfusion injury by targeting TAK1

The FASEB Journal, Journal Year: 2025, Volume and Issue: 39(2)

Published: Jan. 24, 2025

Abstract Liver ischemia–reperfusion (IR) injury is a common complication following liver surgery, significantly impacting the prognosis of transplantation and other surgeries. Betaine‐homocysteine methyltransferase (BHMT), crucial enzyme in methionine cycle, has been previously confirmed pivotal role hepatocellular carcinoma, it also demonstrated that BHMT inhibits inflammation, apoptosis, but its IR remains unknow. Following I/R injury, we found expression was upregulated human transplant specimens, mice hepatocytes. Utilizing knockout mice, established an vivo model with overexpression AML12 cell lines, created vitro hypoxia–reoxygenation model. Our findings reveal deficiency exacerbates leading to increased reactive oxygen species, apoptosis whereas mitigates these effects. We observed c‐Jun N‐terminal kinase (JNK)/p38 signaling pathway by interacting TAK1 inhibiting activity. The application 5z‐7‐ox, inhibitor, reversed worsening activation JNK/p38 associated deficiency. These results demonstrate protects against targeting pathway. suggest may be promising therapeutic target for preventing injury.

Language: Английский

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Carfilzomib inhibits the progression of hepatocellular cancer by upregulating GADD45α expression

Oncology Letters, Journal Year: 2025, Volume and Issue: 29(4), P. 1 - 14

Published: March 4, 2025

Hepatocellular carcinoma (HCC) ranks among the most prevalent and lethal cancers affecting humans. Currently, there are limited effective treatments available for HCC. Carfilzomib, a proteasome inhibitor, is known to exert anti-HCC activities; however, its underlying mechanisms of action remain unclear. In present study, efficacy carfilzomib against HCC was evaluated were explored. Cell Counting Kit-8, 5-ethynyl-2-deoxyuridine staining colony formation assays employed analyze antiproliferative effect on MHCC-97H Huh7 cells. Additionally, flow cytometry used assess cell cycle Transwell evaluate migration invasion. Western blotting utilized examine protein expression levels associated with arrest. Furthermore, short hairpin RNA (shRNA) transfection investigate role DNA damage inducible α (GADD45α) carfilzomib-induced A xenograft tumor model using nude mice activity in vivo. The findings demonstrated that inhibited proliferation, invasion both addition, caused arrest by suppressing cyclin A2, E1 cyclin-dependent kinases 2 4. Carfilzomib also upregulated GADD45α, activated MAPK pathway GADD45α through shRNA abolished growth To conclude, research revealed inhibits progression cells upregulating expression, suggesting could be potential chemotherapeutic agent

Language: Английский

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Proteomics efforts for hepatocellular carcinoma drug development

Clinical Cancer Bulletin, Journal Year: 2024, Volume and Issue: 3(1)

Published: Nov. 19, 2024

Abstract Hepatocellular carcinoma (HCC) is a malignant tumor associated with high global incidence and mortality rates. Proteomics, as platform technology of cellular protein expression, modification, interaction, has provided innovative perspectives on early diagnosis, treatment, targeted drug development for HCC. This review summarizes recent progress in proteomics advancing HCC biomarker discovery, target identification, understanding action mechanisms. Proteomic technologies, including mass spectrometry specific signatures microarrays high-throughput analysis, bioinformatics data interpretation, have profoundly promoted the identification liver cancer-specific biomarkers. These advancements not only facilitate diagnosis but also improve prognostic assessment. Proteomics pivotal expediting discovery new drugs, providing more effective personalized treatment options patients. offers comprehensive overview applications anti-HCC research, serving reference to further advance research domains.

Language: Английский

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Integration of epigenomic and transcriptomic profiling uncovers EZH2 target genes linked to cysteine metabolism in hepatocellular carcinoma

Cell Death and Disease, Journal Year: 2024, Volume and Issue: 15(11)

Published: Nov. 8, 2024

Enhancer of zeste homolog 2 (EZH2), a key protein implicated in various cancers including hepatocellular carcinoma (HCC), is recognized for its association with epigenetic dysregulation and pathogenesis. Despite clinical explorations into EZH2-targeting therapies, the mechanisms underlying role gene suppression HCC have remained largely unexplored. Here, we integrate epigenomic transcriptomic analyses to uncover transcriptional landscape modulated by selective EZH2 inhibition HCC. By reanalyzing data patients, demonstrate that overexpression correlates poor patient survival. Treatment inhibitor tazemetostat restored expression genes involved cysteine-methionine metabolism lipid homeostasis, while suppressing angiogenesis oxidative stress-related genes. Mechanistically, EZH2-mediated H3K27me3 enrichment at cis-regulatory elements transsulfuration pathway genes, which reversed upon inhibition, leading increased chromatin accessibility. Among 16 EZH2-targeted candidate BHMT CDO1 were notably correlated prognosis. Tazemetostat treatment cells reducing levels ferroptosis markers FSP1, NFS1, SLC7A11. Functionally, dose-dependently reduced cell viability peroxidation cells. Our findings reveal novel mechanism controlling susceptibility HCC, providing rationale exploring therapies this malignancy.

Language: Английский

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