Metabolic reprogramming in liver fibrosis

Cell Metabolism, Год журнала: 2024, Номер 36(7), С. 1439 - 1455

Опубликована: Май 31, 2024

Chronic liver diseases, primarily metabolic dysfunction-associated steatotic disease (MASLD), harmful use of alcohol, or viral hepatitis, may result in fibrosis, cirrhosis, and cancer. Hepatic fibrogenesis is a complex process with interactions between different resident non-resident heterogeneous cell populations, ultimately leading to deposition extracellular matrix organ failure. Shifts phenotypes functions involve pronounced transcriptional protein synthesis changes that require adaptations cellular substrate metabolism, including glucose lipid resembling associated the Warburg effect cancer cells. Cell activation are regulated by stress responses, unfolded response, endoplasmic reticulum stress, autophagy, ferroptosis, nuclear receptor signaling. These crucial for inflammatory fibrogenic macrophages, lymphoid cells, hepatic stellate Modulation these pathways, therefore, offers opportunities novel therapeutic approaches halt even reverse fibrosis progression.

Язык: Английский

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Metformin decelerates aging clock in male monkeys

Cell, Год журнала: 2024, Номер 187(22), С. 6358 - 6378.e29

Опубликована: Сен. 12, 2024

Язык: Английский

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Involvement of SIRT1-mediated aging in liver diseases

Frontiers in Cell and Developmental Biology, Год журнала: 2025, Номер 13

Опубликована: Фев. 20, 2025

Liver disease is a significant global health issue, responsible for millions of deaths annually. Aging, characterized by the gradual decline in cellular and physiological functions, impairs tissue regeneration, increases susceptibility to liver diseases, leads health. Silent information regulator 1 (SIRT1), NAD⁺-dependent deacetylase, has emerged as pivotal factor modulating age-related changes liver. SIRT1 preserves function regulating essential aging-related pathways, including telomere maintenance, epigenetic modifications, senescence, intercellular communication, inflammation, mitochondrial function. Notably, levels naturally with age, contributing progression increased vulnerability injury. This review summarizes regulatory role aging its impact on diseases such fibrosis, alcoholic associated (ALD), metabolic dysfunction-associated steatotic (MASLD), steatohepatitis (MASH), hepatocellular carcinoma (HCC). We also discuss emerging therapeutic approaches, activators, gene therapy, nutritional interventions, which are evaluated their potential restore mitigate progression. Finally, we highlight future research directions optimize SIRT1-targeted therapies clinical applications conditions.

Язык: Английский

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Molecular mechanisms in liver repair and regeneration: from physiology to therapeutics

Signal Transduction and Targeted Therapy, Год журнала: 2025, Номер 10(1)

Опубликована: Фев. 8, 2025

Язык: Английский

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Capsaicin and TRPV1: A Novel Therapeutic Approach to Mitigate Vascular Aging

Aging and Disease, Год журнала: 2025, Номер unknown, С. 0 - 0

Опубликована: Янв. 1, 2025

Vascular aging and its associated diseases represent a principal cause of mortality among the global elderly population, making mitigation vascular significant aspiration for humanity. This article explores intersection nature health, focusing on role natural plant, pepper, bioactive compound, capsaicin, in combating aging. By examining molecular cellular mechanisms as well phenotypic alterations blood vessels, we offer comprehensive review effects capsaicin receptor, transient receptor potential vanilloid 1 (TRPV1), within We propose that may serve medication with to slow progress could constitute new strategy treat related disease.

Язык: Английский

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Targeting senescent hepatocytes for treatment of metabolic dysfunction-associated steatotic liver disease and multi-organ dysfunction

Nature Communications, Год журнала: 2025, Номер 16(1)

Опубликована: Март 28, 2025

Senescent hepatocytes accumulate in metabolic dysfunction-associated steatotic liver disease (MASLD) and are linked to worse clinical outcomes. However, their heterogeneity lack of specific markers have made them difficult target therapeutically. Here, we define a senescent hepatocyte gene signature (SHGS) using vitro vivo models show that it tracks with MASLD progression/regression across mouse large human cohorts. Single-nucleus RNA-sequencing functional studies reveal SHGS+ originate from p21+ cells, lose key functions release factors drive progression. One such factor, GDF15, increases circulation alongside burden Through chemical screening, identify senolytics selectively eliminate improve male mice. Notably, SHGS enrichment also correlates dysfunction other organs. These findings establish as drivers highlight potential therapeutic strategy for targeting cells beyond.

Язык: Английский

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The FBP1‐TP53‐NRF2 metabolic switch in metabolic dysfunction‐associated steatohepatitis‐hepatocellular carcinoma progression and senescence reversal

Clinical and Translational Medicine, Год журнала: 2025, Номер 15(4)

Опубликована: Март 30, 2025

Metabolic dysfunction-associated steatohepatitis (MASH) is defined by extensive hepatosteatosis, liver injury, persistent inflammation and fibrosis.1 Around 2% of patients with MASH progress to MASH-related hepatocellular carcinoma (MASH-HCC) every year, indicating the importance as newly emerging HCC aetiology.2 Nonetheless, it not understood how progresses maintained in some without progression HCC. Here, we outline our recently discovered mechanism which energy-dense diets induce hepatocyte senescence, previously presumed prevent progression. Using fructose fat-rich found diet-induced single-strand DNA breaks that lead activation damage response (DDR), culminates TP53 induction its targets p21CIP1 p16INK4a, two cell-cycle inhibitors enter damaged hepatocytes into a state during they cannot proliferate. Interestingly, also leads metabolic enzyme FBP1, identified an AKT inhibitor due ability interact both PP2A catalytic subunit, inactivates AKT.3 By inhibiting AKT, FBP1 acts HCC-specific tumour suppressor,4 stabilization TP53, thereby boosting senescence5 (Figure 1). upregulated MASH, but degraded insulin growth factor-stimulated hepatocytes. phosphorylating MDM2 enhancing degradation,6 downregulation deficiency, allowing senescent re-enter cell cycle. Conversely, upregulation DNA-damaging inhibits phosphorylation GSK3α/β, increasing substrate binding activity these kinases phosphorylate NRF2 β-catenin triggering their degradation, resulting low expression hepatocytes.5 However, sustained stress autophagy disruption accumulation p62/SQSTM1 sequesters major negative regulator NRF2, KEAP1. This results activation, induces ERK1/2-activating EGF PDGF family members phosphorylation-directed TRIM28-dependent degradation discussed above, degradation. On one hand, after oncogene senescence-induced immune surveillance CD8+ T cells clears premalignant tumorigenesis.7 associated fibrosis driven transforming factor-β, promotes immunoglobulin M (IgM) IgA class-switch appearance immunosuppressive plasma inhibit hepatic immunosurveillance.8 hepatocytes, common feature human MASH.9, 10 As find way bypass rapidly HCC.5 Although old age was proposed enhance tumour-promoting smouldering through senescence-associated secretory phenotype,11 FBP1-NRF2 crossregulatory interactions described above seem play more critical role Moreover, lineage tracking studies were able demonstrate malignant directly descend from Other have resumed proliferation new different never senesced.12 Thus, finding ways specifically target re-entered cycle could novel preventives therapeutics. More than years ago, He et al. made important advance identifying progenitor (HcPC) are present collagenase-resistant aggregates livers carcinogen (DEN) treated mice resemble hepatobiliary stem cells.13 recently, Carlessi al., working Australia, used single nucleus (snRNA-seq) technology identify disease-associated (DaHep) fibrotic/cirrhotic can predict progression.14 collaborating Drs Tirnitz-Parker FBP1-TP53-NRF2 axis may account for HcPC daHep frank alterations predictive value. Indeed, correlated promoter hypermethylation gene.5 It remains be seen whether region first undergoes HcPC/daHep at point precedes histologically or radiologically detected work supported National Nature Science Foundation China Li Gu (32470830 92478135), Sichuan Technology Program University Interdisciplinary Innovation Fund Yahui Zhu (82172990 82372838). Michael Karin NIH grants (R01DK133448, R01CA281784 P01CA281819). The authors declare no conflict interest. Not applicable. Data sharing applicable this article datasets generated analyzed current study.

Язык: Английский

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Liver quad culture chip as a model for radiation injury research

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

Опубликована: Апрель 11, 2025

Abstract Both cancer patients receiving radiotherapy and civilians in a mass casualty nuclear event may suffer from radiation induced damage to organ systems. Radiation liver disease (RILD) can cause acute long-term dysfunction that potentially leads death. The objective of this study was ascertain the validity quad-culture chip, micro-physiological system comprising primary human hepatocytes non-parenchymal cells (NPCs), including sinusoidal endothelial cells, hepatic stellate (HSCs), Kupffer as model for RILD. exposure chip resulted DNA cellular senescence NPCs. We observed metabolic dysfunction, inflammation, HSCs activation. Whole genome sequencing revealed gene alterations pathways relevant RILD, well potential efficacy N -acetylcysteine amide (NACA) against NACA exhibited capacity mitigate decreased impact on other pathophysiological changes. CDKN1A miR-34a-5p were validated useful response treatment biomarkers. These findings highlight an effective investigating microenvironment RILD evaluating therapeutic countermeasures

Язык: Английский

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Therapeutic potential of nicotinamide and ABT263 in alcohol‐associated liver disease through targeting cellular senescence

MedComm, Год журнала: 2025, Номер 6(2)

Опубликована: Фев. 1, 2025

Abstract Alcohol‐associated liver disease (ALD) is a major cause of liver‐related morbidity and mortality, yet clinically effective therapies for ALD remain lacking. Here, we demonstrate that alcohol intake its metabolite, acetaldehyde (ACH), induce senescence in the cells, respectively. To assess therapeutic potential targeting ALD, treated ALD‐affected mice with senolytic compound ABT263 senomorphic NAD + precursor, nicotinamide (NAM). The results show effectively clears senescent hepatocytes stellate reduces triglyceride (TG), but increases plasma alanine aminotransferase TG levels. Conversely, NAM efficiently suppresses senescence‐associated secretory phenotype (SASP), protecting from alcohol‐induced injury mice. RNA‐sequencing analysis revealed treatment downregulated genes involved adipogenesis while activating complement pathway. In contrast, upregulated metabolism‐related genes, such as Sirt1 , DNA damage marker including Rec8 E2f1 liver. These findings suggest cellular plays critical role injury. Compared cell clearance by ABT263, suppressing SASP may provide safer more approach ALD.

Язык: Английский

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Combined Exposure of Sleep Deprivation and Environmental Particulate Matter Drives Aging in Multiple Systems

Journal of Hazardous Materials, Год журнала: 2025, Номер 491, С. 137914 - 137914

Опубликована: Март 13, 2025

Язык: Английский

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