Role of CNNM4 in the progression of cholangiocarcinoma: implications for ferroptosis and therapeutic potential.

Background And Objective: Cholangiocarcinoma (CCA) is a heterogeneous neoplasm of the biliary epithelium that easily infiltrates, metastasises and recurs. Magnesium disbalance is a hallmark of CCA, with the magnesium transporter cyclin M4 (CNNM4) being a key driver of various hepatic diseases. This study aims to unravel the role of CNNM4 in the initiation and progression of CCA.

Epigenetic mechanisms in HCC immune landscape: Therapeutic implications.

Hepatocellular carcinoma (HCC) is the most frequent primary liver tumor and is currently a major cause of cancer-related mortality worldwide. The arrival of immune checkpoint inhibitors (ICI), and their combination with anti-VEGF/VEGFR antibodies, has transformed the treatment of patients with advanced HCC. Still, only about 30 % of patients respond to therapy, and these cases are among those displaying an immune-enriched ("immune-hot") tumor microenvironment (TME).

Gut-to-Bile transfer of microbially amidated minor bile acids in patients with hepatopancreatobiliary disorders.

Background Aims: During bile acid (BA) intestinal transit, microbially amidated BAs (MABAs) are produced. This study investigated their cholephilic behavior and their presence in the bile of patients with hepatopancreatobiliary diseases.

Methods: Bile samples were collected during surgical or endoscopic procedures and analyzed using HPLC-MS/MS, with cholic acid (CA) and chenodeoxycholic acid (CDCA) chemically amidated with leucine (Leu), phenylalanine (Phe), or tyrosine (Tyr) as standards.

Expression landscape of epigenetic genes in human hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the most common primary liver tumor, often arising in the context of chronic liver disease. Despite recent advances in systemic therapies, including the use of immune checkpoint inhibitors (ICIs), clinical outcomes remain suboptimal, with many patients exhibiting primary or acquired resistance. Accumulating evidence indicates that the dysregulation of epigenetic mechanisms contributes to HCC development, and may also play a crucial role in shaping the tumor immune microenvironment, influencing responses to treatments.

Epigenetic mechanisms involved in hepatocellular carcinoma development and progression.

Hepatocellular carcinoma (HCC) typically develops in the context of chronic liver disease, where prolonged hepatocyte exposure to inflammation drives the synergistic accumulation of genetic and epigenetic alterations. Epigenetic regulation encompasses multiple mechanisms that govern the transcription machinery accessibility to DNA. This process is regulated by the addition and removal of covalent marks on chromatin, which can either affect DNA-histone interactions or serve as scaffolds for other proteins, among other mechanisms.

A novel noninvasive test based on near-infrared fluorescent cholephilic probes for hepatobiliary secretory function assessment.

Routine serum biomarkers do not always accurately reflect impaired liver function. To overcome this limitation, we synthesized novel bile acid (BA) derivatives (NIRBADs) with near-infrared (NIR) fluorescence that can penetrate the abdominal wall and be detected extracorporeally. NIRBAD dynamics in the liver parenchyma were recorded through intravital imaging in mice and extracorporeally in both rats and mice.

Relevance of transportome among the mechanisms of chemoresistance in hepatoblastoma.

Approximately 20 % of hepatoblastomas (HBs) exhibit a poor response to conventional chemotherapy due to mechanisms of chemoresistance (MOCs), such as reduced intracellular drug accumulation. This study evaluated the role of transportome in the multidrug resistance (MDR) of HB. Paired HB and adjacent liver tissue samples (n = 19) and HB-derived cell lines (HepG2, HuH6) were analyzed for their resistome characterization at mRNA (RT-qPCR, Taqman Low-Density Array, sequencing) and protein (western blot, immunohistochemistry, immunofluorescence) levels.

Mapping the landscape of biliary tract cancer in Europe: challenges and controversies.

Biliary tract cancer (BTC) is becoming more common worldwide, with geographic differences in incidence and risk factors. In Europe, BTC may be associated with primary sclerosing cholangitis, lithiasis, and liver cirrhosis, but is more frequently observed as a sporadic disease. BTC increasingly affects patients under 60 years, resulting in a significant social and economic burden.

Mutational Analysis of Bile Cell-Free DNA in Primary Sclerosing Cholangitis: A Pilot Study.

Background: Primary sclerosing cholangitis (PSC) is a chronic liver disease characterised by inflammation and fibrosis of the bile ducts, conferring an increased risk of cholangiocarcinoma (CCA). However, detecting CCA early in PSC patients remains challenging due to the limited sensitivity of conventional diagnostic methods, including imaging or bile duct brush cytology during endoscopic retrograde cholangiopancreatography (ERCP). This study aims to evaluate the potential of bile cell-free DNA (cfDNA) mutational analysis, termed the Bilemut assay, as a tool for CCA detection in PSC patients.

RNA-based therapies in liver metabolic diseases.

RNA-based therapeutics have rapidly emerged over the past decade, offering a new class of medicines that differ significantly from conventional drugs. These therapies can be programmed to target or restore defective genes, allowing for more personalised treatments and reducing side effects. Notably, RNA therapies have made significant progress in the treatment of genetic liver diseases, exemplified by small interfering RNA treatments for hereditary transthyretin amyloidosis, which use liver-targeting strategies such as GalNAc conjugation to improve efficacy and safety.

Targeting protein hyper-SUMOylation halts cholangiocarcinoma progression by impairing cancer cell viability and tumor-stroma cross talk.

Background And Aims: Cholangiocarcinoma (CCA) includes a diverse group of biliary malignancies with poor prognosis. Alterations in post-translational modifications contribute to disrupted protein dynamics, cellular disturbances, and disease. This study investigates the role of protein SUMOylation in cholangiocarcinogenesis and its potential as a therapeutic target.

FGF21 and APOA1 mRNA-based therapies for the treatment of experimental acute pancreatitis.

Background: Acute pancreatitis (AP) presents a significant clinical challenge with limited therapeutic options. The complex etiology and pathophysiology of AP emphasize the need for innovative treatments. This study explores mRNA-based therapies delivering fibroblast growth factor 21 (FGF21) and apolipoprotein A1 (APOA1), alone and in combination, for treating experimental AP.

Targeting of the G9a, DNMT1 and UHRF1 epigenetic complex as an effective strategy against pancreatic ductal adenocarcinoma.

Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with limited treatment options and a poor prognosis. The critical role of epigenetic alterations such as changes in DNA methylation, histones modifications, and chromatin remodeling, in pancreatic tumors progression is becoming increasingly recognized. Moreover, in PDAC these aberrant epigenetic mechanisms can also limit therapy efficacy.

Quantitative proteomic analysis unveils a critical role of VARS1 in hepatocellular carcinoma aggressiveness through the modulation of MAGI1 expression.

Background: Hepatocellular carcinoma (HCC) genetic/transcriptomic signatures have been widely described. However, its proteomic characterization is incomplete. We performed non-targeted quantitative proteomics of HCC samples and explored its clinical, functional, and molecular consequences.

Loss of protects against MASLD alone or with alcohol intake by preserving lipid homeostasis.

Background & Aims: Expression of P21, encoded by the gene, has been associated with fibrosis progression in steatotic liver disease (SLD); however, the underlying mechanisms remain unknown. In the present study, we investigated the function of CDKN1A in SLD.

Methods: expression levels were evaluated in different patient cohorts with SLD, fibrosis, and advanced chronic liver disease (ACLD).

Modulatory effects of CNNM4 on protein- l -isoaspartyl- O -methyltransferase repair function during alcohol-induced hepatic damage.

Background And Aims: Alcohol-associated liver disease (ALD) is a leading cause of liver-related mortality worldwide, with limited treatment options beyond abstinence and liver transplantation. Chronic alcohol consumption has been linked to magnesium (Mg 2+ ) deficiency, which can influence liver disease progression. The mechanisms underlying Mg 2+ homeostasis dysregulation in ALD remain elusive.

Sensitizing cholangiocarcinoma to chemotherapy by inhibition of the drug-export pump MRP3.

Aims: Drug export through ABC proteins hinders cancer response to chemotherapy. Here, we have evaluated the relevance of MRP3 (ABCC3) in cholangiocarcinoma (CCA) as a potential target to overcome drug resistance.

Methods: Gene expression was analyzed in silico using the TCGA-CHOL database and experimentally (mRNA and protein) in resected CCA tumors.

Systemic messenger RNA replacement therapy is effective in a novel clinically relevant model of acute intermittent porphyria developed in non-human primates.

Objective: Acute intermittent porphyria (AIP) is a rare metabolic disorder caused by haploinsufficiency of hepatic porphobilinogen deaminase (PBGD), the third enzyme of the heme biosynthesis. Individuals with AIP experience neurovisceral attacks closely associated with hepatic overproduction of potentially neurotoxic heme precursors.

Design: We replicated AIP in non-human primates (NHPs) through selective knockdown of the hepatic gene and evaluated the safety and therapeutic efficacy of human PBGD (hPBGD) mRNA rescue.

Comprehensive in silico CpG methylation analysis in hepatocellular carcinoma identifies tissue- and tumor-type specific marks disconnected from gene expression.

DNA methylation is crucial for chromatin structure, transcription regulation and genome stability, defining cellular identity. Aberrant hypermethylation of CpG-rich regions is common in cancer, influencing gene expression. However, the specific contributions of individual epigenetic modifications to tumorigenesis remain under investigation.

Identification of PRMT5 as a therapeutic target in cholangiocarcinoma.

Background: Cholangiocarcinoma (CCA) is a very difficult-to-treat cancer. Chemotherapies are little effective and response to immune checkpoint inhibitors is limited. Therefore, new therapeutic strategies need to be identified.

Caspases compromise SLU7 and UPF1 stability and NMD activity during hepatocarcinogenesis.

Background & Aims: The homeostasis of the cellular transcriptome depends on transcription and splicing mechanisms. Moreover, the fidelity of gene expression, essential to preserve cellular identity and function is secured by different quality control mechanisms including nonsense-mediated RNA decay (NMD). In this context, alternative splicing is coupled to NMD, and several alterations in these mechanisms leading to the accumulation of aberrant gene isoforms are known to be involved in human disease including cancer.