Targeting epigenetic and posttranslational modifications regulating ferroptosis for the treatment of diseases

Signal Transduction and Targeted Therapy, Год журнала: 2023, Номер 8(1)

Опубликована: Дек. 10, 2023

Abstract Ferroptosis, a unique modality of cell death with mechanistic and morphological differences from other modes, plays pivotal role in regulating tumorigenesis offers new opportunity for modulating anticancer drug resistance. Aberrant epigenetic modifications posttranslational (PTMs) promote resistance, cancer progression, metastasis. Accumulating studies indicate that can transcriptionally translationally determine vulnerability to ferroptosis functions as driver nervous system diseases (NSDs), cardiovascular (CVDs), liver diseases, lung kidney diseases. In this review, we first summarize the core molecular mechanisms ferroptosis. Then, roles processes, including histone PTMs, DNA methylation, noncoding RNA regulation such phosphorylation, ubiquitination, SUMOylation, acetylation, ADP-ribosylation, are concisely discussed. The PTMs genesis cancers, NSD, CVDs, well application PTM modulators therapy these then discussed detail. Elucidating mediated by will facilitate development promising combination therapeutic regimens containing or PTM-targeting agents inducers be used overcome chemotherapeutic resistance could prevent addition, highlight potential approaches chemoresistance halt

Язык: Английский

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Sodium aescinate-induced hepatotoxicity via ATF4/GSH/GPX4 axis-mediated ferroptosis

Scientific Reports, Год журнала: 2025, Номер 15(1)

Опубликована: Янв. 7, 2025

Sodium aescinate (SA), a natural plant extract with various bioactivities, is widely used to treat oedema and inflammation in clinics. However, adverse events, including liver injury, kidney phlebitis, have been reported patients SA recent years. In this study, we BALB/c mice L02 cells evaluate the role of ferroptosis SA-induced injury. significantly increased AST, ALT, MDA Fe2+, decreased GSH levels, induced pathological changes vivo. also reduced viability LDH release, intracellular cysteine reduction, depletion, iron accumulation, ROS production, lipid peroxidation, indicating that causes ferroptosis. addition, inhibited transcriptional activity activating transcription factor 4 (ATF4) subsequently expression downstream genes xCT (solute carrier family 7a member 11, SLC7A11) Cystathionine gamma-lyase (CTH) which play vital roles biosynthesis. Interestingly, cytotoxic effects were effectively attenuated by ATF4 overexpression, while they aggravated silencing. These results revealed triggers hepatocyte inhibiting ATF4, an oxidative imbalance.

Язык: Английский

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Treatment of liver fibrosis: Past, current, and future

World Journal of Hepatology, Год журнала: 2023, Номер 15(6), С. 755 - 774

Опубликована: Июнь 25, 2023

Liver fibrosis accompanies the progression of chronic liver diseases independent etiologies, such as hepatitis viral infection, alcohol consumption, and metabolic-associated fatty disease. It is commonly associated with injury, inflammation, cell death. characterized by abnormal accumulation extracellular matrix components that are expressed myofibroblasts collagens alpha-smooth actin proteins. Activated hepatic stellate cells contribute to major population myofibroblasts. Many treatments for have been investigated in clinical trials, including dietary supplementation (e.g., vitamin C), biological treatment simtuzumab), drug pegbelfermin natural herbs), genetic regulation non-coding RNAs), transplantation stem hematopoietic cells). However, none these has approved Food Drug Administration. The efficacy can be evaluated histological staining methods, imaging serum biomarkers, well scoring systems, fibrosis-4 index, aspartate aminotransferase platelet ratio, non-alcoholic disease score. Furthermore, reverse slowly frequently impossible advanced or cirrhosis. To avoid life-threatening stage fibrosis, anti-fibrotic treatments, especially combined behavior prevention, treatment, drugs herb medicines, needed. This review summarizes past studies current future fibrosis.

Язык: Английский

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Bifidobacterium longum promotes postoperative liver function recovery in patients with hepatocellular carcinoma

Cell Host & Microbe, Год журнала: 2023, Номер 32(1), С. 131 - 144.e6

Опубликована: Дек. 12, 2023

Timely liver function recovery (LFR) is crucial for postoperative hepatocellular carcinoma (HCC) patients. Here, we established the significance of LFR on patient long-term survival through retrospective and prospective cohorts identified a key gut microbe, Bifidobacterium longum, depleted in patients with delayed recovery. Fecal microbiota transfer from HCC to mice similarly impacted time post hepatectomy. However, oral gavage B. longum improved repair these mice. In clinical trial patients, orally administering probiotic bacteria cocktail containing reduced rates recovery, shortened hospital stays, overall 1-year survival. These benefits, attributed diminished inflammation, fibrosis, hepatocyte proliferation, were associated changes metabolic pathways, including 5-hydroxytryptamine, secondary bile acids, short-chain fatty acids. Our findings propose that modulation can enhance LFR, thereby improving outcomes

Язык: Английский

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Programmed cell death in hepatic fibrosis: current and perspectives

Cell Death Discovery, Год журнала: 2023, Номер 9(1)

Опубликована: Дек. 12, 2023

Abstract The initiation, development and resolution of hepatic fibrosis are influenced by various cytokines, chemokines, damage-associated molecular patterns (DAMPs) signaling pathways. A significant number studies in recent years have indicated that the progression is closely linked to programmed cell death processes such as apoptosis, autophagy, pyroptosis, necroptosis, ferroptosis, cuproptosis, PANoptosis. Inducement stellate cells (HSCs) or preventing other liver can delay even reverse fibrosis. Nevertheless, roles not been reviewed. Therefore, this review summarizes characteristics death, focuses on latest progress promotion regression fibrosis, highlights different HSCs In end, possible therapeutic approaches targeting for treating discussed prospected.

Язык: Английский

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RNA-seq combined network pharmacology reveals that Fu-Gan-Wan (FGW) inhibits liver fibrosis via NF-κB/CCL2/CCR2 and lipid peroxidation via Nrf2/HMOX1 signaling pathway

Journal of Ethnopharmacology, Год журнала: 2024, Номер 326, С. 117963 - 117963

Опубликована: Фев. 20, 2024

Язык: Английский

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Ghrelin alleviates liver fibrosis by triggering HSCs ferroptosis via regulating injured hepatocyte‐derived exosomal LncMALAT1/GPX4 pathway

The FASEB Journal, Год журнала: 2025, Номер 39(2)

Опубликована: Янв. 21, 2025

Abstract Ghrelin is a gastric peptide that modulates various biological functions, including potential anti‐inflammatory and antifibrotic properties. Increasingly evidence have demonstrated exosomes derived from injured hepatocytes (IHC‐Exo) can accelerate the activation of hepatic stellate cells (HSCs) liver fibrosis. Ferroptosis, type novel programmed cell death, regulates diverse pathological processes, However, it remains unclear whether ghrelin exerts its effect through mechanisms involving ferroptosis. To explore mechanism, IHC‐Exo were isolated supernatant mouse primary (HCs) treated with palmitic acid (PA). Mouse HSCs bile duct ligation (BDL)‐induced fibrosis murine model then or ghrelin‐pretreated (GHR‐IHC‐Exo). The expression α‐SMA, Collagen I long noncoding (lnc) RNA MALAT1 in detected. ferroptosis was evaluated by assessing level CCK8, MDA, GSH, GPX4 expression. serum biopsy samples used to determine involved progression Nanoparticle tracking analysis electron microscopy characterized features IHC‐Exo. As results suggested, compared IHC‐Exo, GHR‐IHC‐Exo treatment significantly promoted HSCs, inhibited their activation, consequently alleviated BDL mice. inhibitory on partially reversed inhibitor Ferrostatin‐1. lncMALAT1 down‐regulated as Serum exosome levels higher patients severe those mild Additionally, suppressor protein elevated progression, indicating decreased In conclusion, reduced pro‐fibrotic regulating lncMALAT1/GPX4 pathway mediated Triggering via may become strategy alleviate

Язык: Английский

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Yunnan medicine Jiangzhi ointment alleviates hyperlipid-induced hepatocyte ferroptosis by activating AMPK and promoting autophagy

Cytotechnology, Год журнала: 2025, Номер 77(2)

Опубликована: Март 5, 2025

Язык: Английский

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Antifibrotic Therapies for Metabolic Dysfunction-associated Steatotic Liver Disease

JHEP Reports, Год журнала: 2025, Номер unknown, С. 101421 - 101421

Опубликована: Апрель 1, 2025

Язык: Английский

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Identification of regulatory cell death-related genes during MASH progression using bioinformatics analysis and machine learning strategies

Frontiers in Immunology, Год журнала: 2025, Номер 16

Опубликована: Май 8, 2025

Background Metabolic dysfunction-associated steatohepatitis (MASH) is becoming increasingly prevalent. Regulated cell death (RCD) has emerged as a significant disease phenotype and may act marker for liver fibrosis. The present study aimed to investigate the regulation of RCD-related genes in MASH elucidate role RCD progression MASH. Methods gene expression profiles from GSE130970 GSE49541 datasets were retrieved Gene Expression Omnibus (GEO) database analysis. A total 101 combinations 10 machine learning algorithms employed screen characteristic differentially expressed (DEGs) that reflect Ontology (GO) Kyoto Encyclopedia Genes Genomes (KEGG) analyses conducted explore enrichment pathways functions feature genes. we performed classification analysis immune infiltration. Consensus cluster was identify subtypes associated with RCD. GSE89632 dataset utilized analyze correlation clinical features DGIdb potential therapeutic drugs compounds targeting In addition, established mouse fibrosis models induced by methionine-choline-deficient (MCD) diet or CCl4 treatment, further validated through quantitative real-time PCR (q-PCR). Lastly, knocked down EPHA3 LX2 cells its effect on TGFb-induced activation cells. Results This discovered 11 RCD-associated DEGs, which predicted Advanced higher levels infiltration significantly correlated DEGs expression. can be classified into two subtypes, 1 2, based these Compared 1, 2 highly shows an increase degree Furthermore, We positively AST ALT levels. Subsequently, also evaluated tissues mice MCD CCl4, results suggested involved development WB showed protein level increased both vitro , observed knocking inhibited TGF-β/Smad3 signaling pathway. Conclusion Our sheds light fact contribute MASH, high lighting targets treating this disease.

Язык: Английский

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