Hepatocellular carcinoma: signaling pathways and therapeutic advances

Signal Transduction and Targeted Therapy, Journal Year: 2025, Volume and Issue: 10(1)

Published: Feb. 6, 2025

Abstract Liver cancer represents a major global health concern, with projections indicating that the number of new cases could surpass 1 million annually by 2025. Hepatocellular carcinoma (HCC) constitutes around 90% liver and is primarily linked to factors incluidng aflatoxin, hepatitis B (HBV) C (HCV), metabolic disorders. There are no obvious symptoms in early stage HCC, which often leads delays diagnosis. Therefore, HCC patients usually present tumors advanced incurable stages. Several signaling pathways dis-regulated cause uncontrolled cell propagation, metastasis, recurrence HCC. Beyond frequently altered therapeutically targeted receptor tyrosine kinase (RTK) involved differentiation, telomere regulation, epigenetic modification stress response also provide therapeutic potential. Investigating key their inhibitors pivotal for achieving advancements management At present, primary approaches (TKI), immune checkpoint (ICI), combination regimens. New trials investigating therapies involving ICIs TKIs or anti-VEGF (endothelial growth factor) therapies, as well combinations two immunotherapy The outcomes these expected revolutionize across all Here, we here comprehensive review cellular pathways, potential, evidence derived from late-stage clinical discuss concepts underlying earlier trials, biomarker identification, development more effective therapeutics

Language: Английский

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Opposite regulation of intestinal and intrahepatic CD8⁺T cells controls alcohol-associated liver disease progression

Gut, Journal Year: 2025, Volume and Issue: unknown, P. gutjnl - 334412

Published: April 8, 2025

Background Gut-liver crosstalk plays an important role in alcohol-associated liver disease (ALD) pathogenesis; but underlying mechanisms remain obscure. Objective We examined the regulation of intestinal and intrahepatic CD8 + T lymphocytes their contribution to ALD. Design ALD patients were recruited for evaluation cells. Single-cell RNA sequencing (scRNA seq) was performed analyse peripheral cells Wildtype, CD8-specific Bcl2 transgenic ( Cd8 Bcl-2 ), −/− mice subjected chronic-plus-binge ethanol feeding. Results In patients, duodenal selectively reduced negatively correlated with injury bacterial translocation markers, while markedly increased. ScRNA seq analysis patient livers revealed several populations expressing activation survival genes (eg, ). Transcriptomics functional studies a key prosurvival BCL2 this opposite Mechanistically, feeding specifically duodenum where levels are high. Inducing reversed ethanol-induced loss cells, improved gut barrier function ameliorated ALD, deficiency linked enhanced neutrophil macrophage infiltration liver, exacerbating mice. Conclusions is associated elevation which aggravates ameliorates respectively. Restoration functions may represent novel therapeutic strategy patients.

Language: Английский

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The Microbiome and Metabolic Dysfunction-Associated Steatotic Liver Disease

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(7), P. 2882 - 2882

Published: March 22, 2025

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a condition wherein excessive fat accumulates in the liver, leading to inflammation and potential damage. In this narrative review, we evaluate tissue microbiota, how they arise their constituent microbes, role of intestinal hepatic microbiota MASLD. The history bacteriophages (phages) occurrence part causation MASLD, conversely, "phage therapy" for antibiotic resistance, obesity, are all described. metabolism bile acids dietary tryptophan histidine defined, together with impacts individual metabolites on MASLD pathogenesis. Both periodontitis dysbiosis may cause microorganisms involved these processes discussed. Novel treatment opportunities involving exist include fecal transplantation, probiotics, prebiotics, synbiotics, supplements, intermittent fasting, phages or holins endolysins. Although FDA yet approve phage therapy clinical use, there multiple FDA-approved trials, represent new horizon future

Language: Английский

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Oral supplementation of choline attenuates the development of alcohol-related liver disease (ALD)

Molecular Medicine, Journal Year: 2024, Volume and Issue: 30(1)

Published: Oct. 18, 2024

Abstract Background Chronic alcohol intake is associated with alterations of choline metabolism in various tissues. Here, we assessed if an oral supplementation attenuated the development alcohol-related liver disease (ALD) mice. Methods Female C57BL/6 J mice (n = 8/group) were either pair-fed a liquid control diet, or Lieber DeCarli diet (5% ethanol) ± 2.7 g choline/kg for 29 days. Liver damage, markers intestinal permeability and microbiota composition determined. Moreover, effects on ethanol-induced ex vivo model. Results ALD as determined by histology assessing inflammation (e.g., nitric oxide, interleukin 6 4-hydroxynonenal protein adducts) was choline. Intestinal small intestine being significantly higher ethanol-fed at level controls receiving In contrast, no found composition. Choline also barrier dysfunction tissue vivo, effect almost entirely abolished oxidase inhibitor dimbunol. Conclusion Our results suggest that attenuates related to protection from dysfunction.

Language: Английский

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Clinical outcomes and associated bacterial and fungal microbiota changes after high dose probiotic therapy for severe alcohol-associated hepatitis: An observational study

Medicine, Journal Year: 2024, Volume and Issue: 103(45), P. e40429 - e40429

Published: Nov. 8, 2024

Alcohol-associated hepatitis (AH) is a critical condition with high mortality rates and worsened by infections. Organ failure strongly associated intestinal dysbiosis. Emerging research suggests that gut microbiota modulation probiotics can improve AH outcomes. This study investigated the clinical microbiome effects of high-dose probiotic infusion (HDPI) compared corticosteroid therapy (CST) fecal transplantation (FMT) in severe AH. Patients biopsy-proven severe-AH were enrolled from March 2019 to June 2020 matched for age disease severity. The patients received HDPI (n = 20), FMT 16), or CST 14). consists potent mix delivered via nasoduodenal tube 6 days. primary outcome was survival at 90-days. Stool samples subjected 16S 18S rRNA sequencing assess significant bacterial fungal taxa their interactions baseline post treatment. At 90-days, 55%, 64.3%, 87.5% (HDPI, CST, respectively). did not beneficially impact alpha-diversity but significantly altered beta-diversity. Notably, number pathogenic bacteria, such as Bilophila Roseburia increased. Fungal analysis revealed no changes alpha diversity, dissimilarities beta diversity post-HDPI. New genera Basidiomycota Phragmoplastophyta have emerged, deleterious expansion communities damaging modifications between fungal-bacterial interactions. failed outperform improving outcomes While influenced both microbiomes, it also led persistence communities. showed superior outcomes, highlighting urgent need further controlled trials.

Language: Английский

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Interplay of Oxidative Stress, Gut Microbiota, and Nicotine in Metabolic-Associated Steatotic Liver Disease (MASLD)

Antioxidants, Journal Year: 2024, Volume and Issue: 13(12), P. 1532 - 1532

Published: Dec. 14, 2024

Oxidative stress has been described as one of the main drivers intracellular damage and metabolic disorders leading to syndrome, a major health problem worldwide. In particular, free radicals alter lipid metabolism promote accumulation in liver, existing hepatic facet dysfunction-associated steatotic liver disease (MASLD). Recent literature highlighted how nicotine, especially if associated with high-fat diet, exerts negative effect on induction progression MASLD by upregulating inflammation increasing oxidative stress, abdominal fat lipolysis, lipogenesis. Moreover, considerable evidence shows central role intestinal dysbiosis pathogenesis impact nicotine-induced gut microbiome. This results an intricate network which stands at intersection point between microbiome, MASLD. The aim this review is delve into molecular mechanisms linking tobacco smoking MASLD, focusing microbiota modifications their development.

Language: Английский

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Aldehydes, mitophagy, and the pathogenesis of alcohol-associated and metabolic dysfunction-associated steatohepatitis

Elsevier eBooks, Journal Year: 2024, Volume and Issue: unknown, P. 329 - 361

Published: Nov. 29, 2024

Language: Английский

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