Liver cancer international最新文献

The ubiquitin–proteasome system (UPS) and autophagy are the two primary cellular pathways for degrading the Z mutant in Alpha 1-Antitrypsin Deficiency (AATD). These degradation pathways maintain hepatic cellular proteostasis in the context of AATD-mediated liver disease. Although alterations in proteasomal degradation have been demonstrated in AATD mouse models, the role of the UPS pathway in AATD-mediated liver disease remains poorly understood. Here, we show that the master regulator of proteostasis, nuclear factor erythroid 2-like 1 (NFE2L1 or NRF1), is activated in response to proteasome impairment caused by the Z variant, mediating proteasome recovery. Under basal conditions, this proteasome bounce-back response is sufficient to compensate for the impairment caused by Z variant expression. However, the NRF1–proteasome axis is downregulated in cirrhotic livers from AATD patients, suggesting that reduced NRF1 activity may contribute to the progression of AATD-associated liver disease. Our findings supported the involvement of the NRF1–proteasome axis in the hepatic proteotoxic response to Z-AAT and highlighted it as a potential therapeutic target to mitigate or prevent AATD-related liver injury.

Alpha-1 antitrypsin (AAT) deficiency is a monogenetic condition caused by various single mutations in the SERPINA1 gene. Homozygous carriage of the Z allele (Pi*ZZ) increases the risk of pulmonary emphysema and liver cirrhosis. Z-AAT polymerises and accumulates in hepatocytes, causing liver damage. Secretion of Z-AAT polymers into the circulation is thought to contribute to lung inflammation. Fibrinopeptide Aα-Val⁵⁴¹ is a biomarker of neutrophil-derived proteinase 3 (PR3) enzyme activity, which is inhibited by AAT. We hypothesised that liver transplantation (LT), which results in normal levels of circulating wild-type AAT, reduces circulating polymers and Aα-Val⁵⁴¹ in Pi*ZZ individuals. Plasma was obtained from five Pi*ZZ individuals before and after LT. Z-AAT polymers were measured using a mouse monoclonal antibody (LG96), and fibrinopeptide Aα-Val⁵⁴¹ levels were assessed using a Europium-based immunoassay. After transplantation, polymers were absent or nearly absent, and Aα-Val⁵⁴¹ levels were substantially reduced. Circulating polymers and Aα-Val⁵⁴¹ levels were markedly reduced in Pi*ZZ individuals receiving a LT.

The hepatic steatosis index (HSI) is used to detect steatotic liver disease (SLD), but its diagnostic performance in African populations is unknown. We performed an external validation of HSI among adults in Zambia. We consecutively screened treatment-naïve people with HIV and individuals without HIV in Zambia using the controlled attenuation parameter (CAP) by vibration controlled transient elastography (VCTE). Model discrimination and calibration were assessed using the c-index and calibration plots. Among 401 participants, 161 (40.1%) were people with HIV. Median age was 37 years (interquartile range 32–43), 244 (60.9%) were female, and 131 (32.7%) were overweight or obese. VCTE-confirmed SLD was present in 41 (10.2%) participants, whereas 92 (22.9%) had an HSI ≥ 36. The c-index to diagnose SLD was 0.67 (95% confidence interval 0.56–0.77). The calibration plot indicated that HSI overestimated the risk for SLD. HSI showed a poor diagnostic performance for the detection of SLD among adults in Zambia.

Under the new steatotic liver disease (SLD) framework, alcohol-related liver disease (ALD) is defined including two subtypes: (1) people with cardiometabolic risk factors (CMRFs) and with alcohol consumption > 50/60 g/day (for female/male), noted as ALD-1, and (2) people with daily alcohol consumption > 20/30 g/day but without CMRF, noted as ALD-2. However, little is known about the difference between these subtypes. Using UK biobank data, we identified individuals with ALD-1 and ALD-2 using the standard definition. We compared the two groups on their socioeconomic status, clinical characteristics, and mortality. Among 11 583 participants with ALD, only 17 (0.15%) had ALD-2. Compared to ALD-1, those with ALD-2 were more likely to be non-White, socioeconomically deprived, and smokers, with higher levels of ALT, AST, GGT, and FIB4 scores. The mortality rate was significantly higher in ALD-2 than ALD-1 (31.9 vs. 11.3 per 1000 person-years, HR 2.45 (95% CI 1.09, 5.50)). ALD-1 and ALD-2 exhibit substantial heterogeneity in socioeconomic status, lifestyle factors, clinical characteristics, and prognoses, suggesting distinct underlying mechanisms. These findings highlight the need for tailored management strategies that address the unique characteristics of each subtype.

Loss of effective arterial blood volume, secondary hyperaldosteronism, adrenergic activation and nonosmotic hypersecretion of vasopressin induce sodium and water retention in cirrhotic patients with ascites. The mechanisms of sodium retention that precede ascites formation remain elusive. In patients who are at the preascites stage of cirrhosis, no sign of reduced effective volaemia is found; nonetheless, tubular sodium retention is already present. Maturation and full functionality of epithelial sodium channels (ENaC) in distal segments of the nephron and, therefore, final control of sodium excretion are dependent on regulated proteolysis by proprotein convertases. Evidence of abnormal or incomplete maturation of ENaCs in preascitic cirrhosis exists, but the complex mechanisms of regulated proteolysis leading to ENaC maturation through sequential action of serine endopeptidases (i.e., furin, site-1 protease, prostasin, plasmin) have never been studied in liver cirrhosis. Also, the mechanisms of cirrhosis-associated immune dysfunction, which are characterised by systemic sterile inflammation and release of proinflammatory cytokines that profoundly influence renal function, remain largely unknown. Release of proinflammatory cytokines and functions of respective receptors are controlled through regulated proteolysis by cell membrane metallopeptidases (mainly ADAM-10 and -17). Once again, little is known in preascitic cirrhosis about potential disregulated proteolysis of proinflammatory cytokines that may trigger systemic inflammation and renal dysfunction. We advance a new hypothesis that (a) may link proprotein convertases to disregulated proteolysis of tubular sodium channels, renin-angiotensin system receptors and inflammatory mediators, and that (b) may shed light on the mechanisms of sodium retention before any systemic neurohormonal activation in liver cirrhosis.

Metabolic-associated steatotic liver disease (MASLD) is among the most prevalent liver disorders worldwide, with many patients progressing to metabolic-associated steatohepatitis (MASH) characterised by fibrosis and inflammation. The current lack of effective treatments for MASH highlights the urgent need to deepen our understanding of its underlying mechanisms. Examining cellular dynamics—specifically, changes in cell type proportions across disease stages—offers a promising avenue for gaining such insights. However, previous deconvolution analyses have been limited to a few cell types, and a comprehensive analysis encompassing diverse cell populations and their unique subtypes has yet to be conducted. In this study, we employed MuSiC deconvolution to analyse two bulk RNA sequencing datasets spanning the MASLD spectrum across both fibrosis staging and Non-Alcoholic Fatty Liver Disease Activity Score (NAS) staging. Our analysis reveals distinct proportional trends in 10 different cell types, including hepatocytes, cholangiocytes, two subpopulations of hepatic stellate cells, endothelial cells, and immune cells such as kupffer cells, TREM2⁺ macrophages, and plasma B cells. In addition to deconvolution analysis, we integrated cell type proportion data with transcriptomic profiles, significantly enhancing the performance of random forest models in classifying fibrosis stages compared to using transcriptomic data alone. The study's findings highlight critical cellular dynamic changes across MASLD progression, advancing our understanding of the disease mechanisms and potentially informing the development of more effective therapeutic strategies.

The clinical utility of comprehensive genomic profiling (CGP) in intrahepatic cholangiocarcinoma (ICC) remains to be fully elucidated. This study analysed CGP test results and evaluated treatment outcomes with fibroblast growth factor receptor (FGFR) inhibitors in patients with ICC, aiming to assess their efficacy in cases with specific FGFR alterations and to explore how CGP can inform personalised treatment strategies. We retrospectively reviewed clinical data from 52 patients with pathologically confirmed advanced ICC, who successfully underwent the CGP test at a Japanese cancer referral centre between November 2019 and March 2023. The median patient age was 67 years. CGP test identified one patient (1.9%) with a high tumour mutation burden (TMB) and revealed therapeutically relevant oncogenic driver gene alterations in 32.7% of cases. The most frequently detected alterations were FGFR2 alterations (15.4%) and isocitrate dehydrogenase 1 mutations (9.6%). Based on CGP results, nine patients—eight with FGFR2 fusions or rearrangements and one with high TMB—were eligible for approved targeted therapies. Among these, four patients treated with pemigatinib achieved stable disease, with a median treatment duration of 244 days. Notably, one patient with an FGFR2 fusion responded to pemigatinib following futibatinib failure. CGP test, when implemented in a timely manner, can serve as a valuable tool in clinical practice for identifying novel therapeutic options for patients with advanced ICC. Furthermore, sequential therapy with FGFR inhibitors may be an effective strategy for managing patients with FGFR2 fusions or rearrangements.

Alpha-1 antitrypsin deficiency (A1ATD) is an inherited metabolic disorder caused by a mutation (ZZ) in the SERPINA1 gene. Carriers are predisposed to liver and lung pathology. The severity of A1ATD-associated liver disease is highly variable, necessitating further characterisation. This study aims to investigate the risk and extent of liver disease and the prevalence of liver transplantation in ZZ A1ATD patients. Several established databases, including Ovid, EBSCO, PubMed, and Cochrane Library, were searched from inception to May 12, 2024. Data were pooled using a random effects model, and study weight was calculated using the inverse variance method. Crude odds ratios (cOR) were calculated using participants with the MM genotype as the comparator. The study was registered in PROSPERO (CRD42022335666). Of the 4420 studies identified, 45 studies and 8638 A1ATD patients (38.8% female) were included. ZZ A1ATD patients demonstrate an increased risk of liver diseases compared to controls, including steatosis (crude odds ratio (cOR): 1.52 [95% CI: 1.21, 1.91]), fibrosis (cOR: 9.85 [95% CI: 5.70, 17.03]), cirrhosis (cOR: 10.43 [95% CI: 5.51, 19.73]), and liver cancers (cOR: 14.12 [95% CI: 6.50, 30.66]). The prevalence of liver transplantation is considerable, with rates reaching 5% [95% CI: 0.00, 12.34]. Our findings confirm the substantial burden of liver disease in ZZ A1ATD patients, including subclinical manifestations such as steatosis and fibrosis that may remain undetected. Given the lack of approved treatments for A1ATD-associated liver disease, prioritising the development of novel therapies to stop or reverse liver disease is essential.

MSDC-0602 K is a second-generation insulin sensitizer that inhibits the mitochondrial pyruvate carrier without activating the transcription factor PPARγ. The EMMINENCE phase IIb trial evaluated MSDC-0602 K in patients with metabolic dysfunction-associated steatohepatitis (MASH). MSDC-0602 K missed statistical significance on endpoints based on liver histology while producing significant reductions in metabolic biomarkers. Here, we assessed the extracellular matrix-based biomarkers PRO-C3 and PRO-C6, surrogates of collagen type III synthesis and the profibrotic, pro-inflammatory fragment endotrophin. 392 MASH patients were randomised to placebo (PL), 62.5 mg, 125 mg or a 250 mg daily dose of MSDC-0602 K for 12 months. 334 completed the study. The primary efficacy endpoint was defined as an improvement of ≥ 2 points in NAS score, with ≥ 1 decrease in either ballooning or inflammation and no increase in fibrosis stage. Blood samples were collected at baseline, 6 months, and 12 months to assess biochemical markers PRO-C3 and PRO-C6. The 125 mg and 250 mg doses of MSDC-0602 K reduced PRO-C3 at 6 months (p = 0.0103 and p = 0.026 respectively) and 12 months (p = 0.0274 and p = 0.0311) compared to placebo. Furthermore, the 62.5 mg and 250 mg doses reduced PRO-C6 at 12mo (p = 0.0467 and p = 0.0266) compared to placebo. Treated patients who reached the primary endpoint had lower baseline PRO-C3 (p = 0.026), and PRO-C3 levels discriminated between regressing, stable or progressing fibrosis (p = 0.0076). MSDC-0602 K significantly reduced PRO-C3 and PRO-C6, suggesting anti-fibrotic and pro-metabolic effects. Lower baseline fibroblast activity (PRO-C3) at baseline was associated with improvement in fibrosis, while higher baseline PRO-C3 was associated with fibrosis progression. Our findings suggest that MSDC-0602 K has anti-fibrogenesis and pro-metabolic effects not detected by liver histology.

Trial Registration: EMMINENCE clinical trial number (ClinicalTrials.gov NCT02784444)

Hepatocellular carcinoma (HCC) is a major cause of cancer-related deaths worldwide. Therapeutic options are limited, and therefore new therapeutic targets are needed. Cathepsins, lysosomal proteases, are implicated in various types of cancer. While intracellular cathepsins have various physiological functions, their extracellular secretion can lead to pathological effects. Cathepsin B (CTSB) stays active at neutral pH and contributes to several liver pathologies, including HCC. However, the mechanisms by which extracellular CTSB contributes to HCC remain unclear. Hence, this study aimed to investigate the role of extracellular CTSB in HCC. Cell and spheroid viability of HepG2 and Huh-7 cells was assessed after treatment with extracellular and intracellular CTSB inhibitors. A chorioallantoic membrane HCC xenograft model was used to study the effect of combined extracellular CTSB inhibitor and chemotherapy treatment on tumour growth, apoptosis, proliferation and angiogenesis. The UK Biobank proteomics data was used to determine the potential role of CTSB in HCC patients. Inhibition of extracellular CTSB significantly decreased the viability of HepG2 and Huh-7 cells in both monolayers and spheroids compared to intracellular CTSB inhibition. The chorioallantoic membrane model demonstrated that extracellular CTSB inhibition decreased the ratio of proliferation-apoptosis and, in the presence of paclitaxel, tumour angiogenesis, which resulted in a smaller tumour mass. Furthermore, compared to healthy controls, HCC patients demonstrated higher plasma levels of CTSB which were associated with a higher mortality risk. In conclusion, targeting extracellular CTSB could be a promising therapeutic strategy for HCC, since it decreases angiogenesis and proliferation, while it increases apoptosis.