A visible-light-induced pyridylation-thioesterification of alkenes with 4-cyanopyridines and thioacids has been developed. This transformation could provide a series of structurally diverse β-pyridyl-thioesters in moderate to good yields at room temperature. The advantages of this protocol are highlighted by its characteristics of clean energy source, mild conditions, and good compatibility of functional groups. Notably, β-pyridyl-thioesters have exhibited significant inhibitory activities against human hepatoma cell line (HepG2).

Hepatocellular carcinoma (HCC) is the fastest growing cause of cancer-related mortality and there are limited therapies1. Although endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) are implicated in HCC, the involvement of the UPRtransducer ATF6α remains unclear2. Herewe demonstrate thefunction ofATF6α as an ER-stress-inducing tumour driver and metabolic master regulator restricting cancer immunosurveillance for HCC, in contrast to its well-characterized role as an adaptive response to ER stress3. ATF6α activation in human HCC is significantly correlated with an aggressive tumour phenotype, characterized by reduced patient survival, enhanced tumour progression and local immunosuppression. Hepatocyte-specific ATF6α activation in mice induced progressive hepatitis with ER stress, immunosuppression and hepatocyte proliferation. Concomitantly, activated ATF6α increased glycolysis and directly repressed the gluconeogenic enzyme FBP1 by binding to gene regulatory elements. Restoring FBP1 expression limited ATF6α-activation-related pathologies. Prolonged ATF6α activation in hepatocytes triggered hepatocarcinogenesis, intratumoural T cell infiltration and nutrient-deprived immune exhaustion. Immune checkpoint blockade (ICB)4 restored immunosurveillance and reduced HCC. Consistently, patients with HCC who achieved a complete response to immunotherapy displayed significantly increased ATF6α activation compared with those with a weaker response. Targeting Atf6 through germline ablation, hepatocyte-specific ablation or therapeutic hepatocyte delivery of antisense oligonucleotides dampened HCC in preclinical liver cancer models. Thus, prolonged ATF6α activation drives ER stress, leading to glycolysis-dependent immunosuppression in liver cancer and sensitizing to ICB. Our findings suggest that persistently activated ATF6α is a tumour driver, a potential stratification marker for ICB response and a therapeutic target for HCC.

Rising numbers of organ failures have intensified the demand for high-performance biomaterials to support the development of bioartificial organs and advanced bioreactors. Hollow fiber membranes (HFMs) are particularly well-suited for such applications, including bioartificial kidney, liver, and 3D cell culture systems, due to their unique architecture and functional versatility. In this study, we engineered HFMs by blending amphiphilic Pluronic F127 (PF127) with poly(ether sulfone) (PES), aiming to enhance both separation efficiency and cellular attachment and proliferation. Physicochemical characterization revealed that PF127 incorporation resulted in a concentric, porous membrane structure with significantly improved porosity as compared to that of plain PES HFMs. Biocompatibility was assessed using human embryonic kidney (HEK293) and hepatocellular carcinoma liver (HepG2) cell lines. Confocal microscopy, MTT cell viability assays, flow-cytometry-based live/dead assays, and calcein AM/propidium iodide staining demonstrated that PF127/PES HFMs strongly support the attachment and proliferation of viable cells. The attached cells exhibited high metabolic activity and formed three-dimensional spheroids, indicating the bioactive influence of PF127. Hemocompatibility evaluation by hemolysis and terminal complement complex (SC5b9) showed that the HFMs fabricated were hemocompatible, suggesting a diminished inflammatory response. Additionally, separation performance evaluation demonstrated a high ultrafiltration coefficient, highest for 2.5 PF127 (173.83 ± 7.31 mL m-2 h-1 mmHg-1) and efficient removal of a broad range of uremic toxins, including urea, creatinine, macroglobulin analogs, and protein-bound toxins such as indoxyl sulfate. Collectively, the enhanced cytocompatibility with kidney and liver cells, hemocompatibility, and separation capability of PF127/PES HFMs make them promising scaffolds for bioartificial kidney and liver applications.

Ethylene glycol (EG), a widely used industrial compound, has been implicated in accidental poisoning and homicide. Although the nephrotoxic mechanisms of EG are well characterized, its acute hepatotoxic potential remains underexplored.This study investigated histopathological and molecular alterations in the liver of rats following acute administration of EG. Possible dysfunction of an anti-oxidative pathway involving ferroptosis (glutathione peroxidase 4, Gpx4; solute carrier family 7 member 11, SLC7A11) is also examined. Male rats (8-week-old, male) were orally administered EG (8g/kg) and euthanized at 2 and 5days post-exposure by an administration of an overdose of anesthetic (40mg/kg sodium pentobarbital). Serological analysis was performed to assess liver function. Liver tissues were evaluated by histology, transmission electron microscopy, and transcriptome analysis. Serological findings indicated transient liver damage at 2days post-exposure, followed by recovery at 5days. Transmission electron microscopy revealed glycogen accumulation, corroborated by periodic acid-Schiff and periodic acid-methenamine silver staining. Histological analysis revealed an increased number of nucleoli, correlating with upregulation of ribosomal genes on microarray analysis, particularly at 5days post-exposure. In addition, significant decreases in Gpx4 and SLC7A11 expression were observed in rat livers treated with EG and Huh-7 human hepatoma cells, suggesting reduced cellular antioxidative capacity as a contributing factor to transient liver damage. These findings reveal a pathway underlying EG-induced transient liver damage and suggest a possible mechanism of recovery, thereby providing new insights into EG poisoning.

Multimodal cascade-amplified phototheranostics for enhanced anti-tumor immunity.

Chemical composition, antiproliferative, and cell death potential of crude and digested jabuticaba (Myrciaria cauliflora) leaf extracts in HepG2 human hepatocellular carcinoma cells in 2D and 3D culture: a bioprospecting approach.

One-step formation of plasmid DNA-loaded lipid-inorganic salt nanoparticles optimized via two-step design of experiments.

Discovery of novel sophocarpine derivatives as potential dual Bcl-2 and Mcl-1 inhibitors: design, synthesis and anti-hepatocellular carcinoma evaluation.

A new snyderane-type sesquiterpene, argusene (1), and 10 known terpenes, 3,3-dimethyl-5-methylene-4-(3-methylpenta-2,4-dien-1-yl)cyclohex-1-ene (2), luzonensol (3), palisadin B (4), 12-hydroxypalisadin B (5), 12-acetoxypalisadin B (6), palisadin A (7), aplysistatin (8), pacifigorgiol (9), debromolaurinterol (10), and 3-bromobarekoxide (11), were isolated from the sea hare Aplysia argus collected from Ikei Island in Okinawa Prefecture, Japan. Their structures were established using spectroscopic methods such as infrared, nuclear magnetic resonance, and high-resolution-electrospray ionization-mass spectrometry. Since all these compounds were derived from a particular red alga, it was determined that this sea hare targets this red alga for feeding, thereby confirming a specific dietary relationship. The cytotoxicity of 1-11 against the human hepatoma cell line HepG2 was evaluated, and 1, 4, 5, 6, 7, 8, 10, and 11 decreased cell viability in a concentration-dependent manner. In addition, intracellular lipid accumulation induced by free fatty acid treatment in serum-free medium was significantly suppressed in the presence of 8 (5.0 µg/mL).

The DNA mismatch repair (MMR) system plays a critical role in maintaining genomic integrity and preventing tumorigenesis. Although MutS homolog 2 (MSH2) is a key component of the MMR system and is dysregulated in human hepatocellular carcinoma (HCC), the molecular mechanism of MSH2 in the process of HCC development under chronic inflammatory conditions remains unclear. To investigate the function of MSH2 in inflammation-associated hepatocarcinogenesis, we treated hepatocyte-specific Msh2-knockout (Msh2 KO) mice with 0.02% thioacetamide for 30 weeks to induce chronic liver inflammation and examined their phenotype. Msh2 KO mice exhibited higher liver tumor incidence than wild-type mice, with no major differences in inflammation or fibrosis. Whole-exome sequencing analysis revealed that genetic alterations with defective MMR-associated signatures were increased in Msh2 KO tumors, though no common cancer driver genes were identified. Transcriptome analysis revealed enrichment of cell cycle-related gene sets, including the G2M checkpoint and E2F targets. Functional assays further demonstrated that MSH2 downregulation impaired ATM-CHK2-mediated DNA damage response and promoted cell cycle acceleration. MSH2 exerts its tumor-suppressive effects in hepatocytes not only through canonical MMR but also by regulating the cell cycle via the ATM-CHK2 axis.

Melanoma-associated antigens (MAGEs) are cancer-testis antigens (CTAs) aberrantly expressed in multiple cancer types, including hepatocellular carcinoma (HCC), and associated with aggressive phenotypes. Although MAGE proteins are widely studied as cancer immunotherapy targets, their roles in HCC and the regulation of their expression during liver pathogenesis in mouse models, including dietary effects, remain poorly understood. We analyzed Mage gene expression in liver tissues from 78 C3H/HeJ mice with chronic diet-induced obesity. While type I MAGE genes are frequently expressed in human HCC, we found no evidence of their expression in mouse liver tumors, suggesting species-specific regulation. In contrast, type II Maged2, previously reported to be upregulated in human HCC, was significantly increased in mouse liver tumors. Analysis of human HCC samples from The Cancer Genome Atlas (TCGA) database confirmed MAGED2 upregulation and its association with patient prognosis. Together, these findings identify MAGED2 as a conserved marker of liver cancer in both humans and mice and emphasize the importance of cross-species comparative approaches for selecting appropriate models and accurately interpreting results, particularly for CTAs, which often evolved recently and in a species-specific manner.

BACKGROUND Hepatocellular carcinoma (HCC) is among the most prevalent cancers worldwide. Recent studies have indicated that 5-methylcytosine (m5c) RNA modifications play crucial roles in various biological processes through interactions with specific regulatory factors, including their involvement in the malignant progression of multiple tumors. AIM To examine the impact of NOP2/sun RNA methyltransferase 5 (NSUN5), an m5c methyltransferase, on the functional behavior of HCC cells. METHODS NSUN5 expression in HCC and normal liver tissues was analyzed using the Gene Expression Profiling Interactive Analysis bioinformatics tool. Human normal hepatocytes (LO2) and HCC cells were examined. The m5c levels in cellular extracts and culture supernatants were quantified using enzyme-linked immunosorbent assay, while NSUN5 levels were quantified using quantitative reverse transcription polymerase chain reaction (for mRNA levels) and Western blotting (for protein levels). Changes in NSUN5 expression following silencing of NSUN5 using transfection with short hairpin RNA were determined. Functional assays were used to evaluate HCC cell growth (Cell Counting Kit-8 and Colony Formation Assays), migration and invasion (Transwell and Wound-Healing Assays), and cell cycle and apoptosis (flow cytometry). RESULTS NSUN5 mRNA was significantly upregulated in HCC compared with normal liver tissues, with expression levels varying across different HCC stages (P < 0.05). HCC cells – HepG2, HEP3B, Huh-7, SMMC7721, and SK-HEP-1 – showed significantly higher NSUN5 mRNA expression levels than the normal human hepatocyte line LO2 (P < 0.05). Following short hairpin RNA-mediated NSUN5 silencing, HepG2 and SMMC7721 cells exhibited reduced proliferation and growth, decreased migration and invasion, and enhanced apoptotic levels (P < 0.05); however, they showed no significant changes in cell cycles (P > 0.05). CONCLUSION Both HCC tissues and cell models consistently demonstrated elevated NSNU5 mRNA and protein expression. Genetic inhibition of the m5c methyltransferase NSUN5 suppresses HCC cell growth, reduces invasiveness and migration, and induces apoptosis.

RNA interference (RNAi) therapeutics targeting hepatitis B virus (HBV) RNAs and monoclonal antibodies (mAbs) targeting HBV surface antigen (HBsAg) represent potential strategies for enabling functional cure in chronic HBV patients. Tobevibart (VIR-3434) is an investigational, Fc-engineered human mAb that targets HBsAg with pan-genotypic neutralizing activity. Elebsiran (VIR-2218) is an investigational small interfering RNA targeting a conserved region of the HBV genome. The in vitro antiviral activity of elebsiran was assessed in HBV-infected primary human hepatocytes and hepatoma cells and showed potent inhibition of viral markers HBeAg (EC50 of 2.5 nM and 53.7 pM, respectively) and HBsAg (EC50 of 1.4 nM and 66.5 pM, respectively). Tobevibart and elebsiran activity in vivo was determined using two well-established HBV mouse models: AAV-HBV transduced C57BL/6 mice and human liver-chimeric mice. Mice were treated with a monotherapy or a combination of muHBC34 (the murinized parental mAb of tobevibart) and elebsiran at different doses. In both models, the mouse surrogate of tobevibart or elebsiran monotherapy was effective in reducing blood HBsAg levels. Combined treatment improved suppression of HBsAg (maximum mean reductions of 2.81 log in the AAV-HBV model and 2.51 log in human liver-chimeric mice) and HBV DNA over monotherapy. Tobevibart and elebsiran have been tested in clinical trials for the treatment of chronic hepatitis B and chronic hepatitis Delta.

Loss of TFAM accelerates pentose phosphate pathway by unleashing G6PD oligomerization to drive hepatocarcinogenesis.

To analyze the expression pattern of Exoribonuclease Family Member 3 (ERI3) in hepatocellular carcinoma (HCC) tissues and its influences on long-term prognosis and cancer cell metastasis. Based on the TCGA-LIHC dataset (including 377 HCC and 50 adjacent normal tissues), the differential expression of ERI3 was analyzed using DESeq2, and the results were validated using immunohistochemical data from the HPA database. A protein-protein interaction network was constructed using STRING and GeneMANIA. The prognostic value of ERI3 was assessed by Cox regression and Kaplan-Meier (KM) survival analyses, its diagnostic efficacy evaluated by ROC curve analysis, and its correlation with immune infiltration analyzed with ssGSEA algorithm. A nomogram prognostic model was established using multivariate Cox regression. For functional validation of ERI3 in vitro, a human HCC cell line SMMC-7721 with ERI3 knockdown was constructed, and the changes in cell proliferation, migration, and invasion were assessed using CCK-8, colony formation, wound healing, and Transwell assays. ERI3 was significantly overexpressed in HCC tissues (P<0.001) and its expression levels increased progressively with advanced TNM stages (T1-T4: P<0.001). In HCC patients, high ERI3 expressions were correlated with a reduced overall survival (HR=2.86, 95% CI: 1.68-4.88; P<0.001), disease-specific survival (HR=2.27, P=0.013), and progression-free interval (HR=1.83, P=0.012). Diagnostic efficacy analysis revealed an AUC of 0.955 (95% CI: 0.931-0.978) for ERI3. Immune infiltration studies demonstrated a positive correlation of ERI3 expression level with Th2 cells (r=0.340, P<0.001) and a negative correlation with Th17 cells (r=-0.284, P<0.001). Multivariate Cox regression analysis identified ERI3 as an independent prognostic factor for HCC (HR=1.987, P=0.003), and the constructed nomogram showed a good predictive accuracy (C-index=0.668). In SMMC-7721 cells, ERI3 knockdown significantly suppressed cell proliferation, migration, and invasion. ERI3 overexpression promotes HCC cell proliferation, migration, and invasion and is strongly linked to a poor prognosis of the patients.

Following the publication of the above paper, it was drawn to the Editor's attention by a concerned reader that certain of the flow cytometric data shown in Fig. 3C, the immunohistochemical data shown in Fig. 4B and the western blots in Fig. 5B had already been submitted to, or were published in, articles in other journals that featured some of the same authors; moreover, some of these data subsequently appeared in different articles in other journals that were not connected with either this research group or this research topic. Upon investigating these issues further in the Editorial Office, it was noted that, concerning Figs. 3‑5 and as far as those papers sharing some of the same authors was concerned, the cases of data sharing weren't necessarily as simple as the data merely being duplicated. Given the sharing of these contentious data across a number of different journals, the Editor of Oncology Reports has decided that this paper should be retracted from the Journal on account of a lack of confidence in the presented data. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive a reply. The Editor apologizes to the readership for any inconvenience caused. [Oncology Reports 32: 1571‑1577, 2024; DOI: 10.3892/or.2014.3386].

Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality. It usually arises in cirrhotic liver, where chronic inflammation and fibrosis create a tumor-permissive microenvironment. Dysregulation of microRNAs (miRNAs), particularly upregulation of the oncomiR miR-221 and loss of the tumor suppressor miR-199a-3p represent key drivers of liver carcinogenesis. The TG221 transgenic mouse, designed to overexpress miR-221 in hepatocytes, provides a relevant in vivo platform for mechanistic studies and for testing preventive and therapeutic approaches. The TG221 model recapitulates miR-221-driven tumorigenesis, including suppression of p27, p57 and Bmf. It is characterized by steatohepatitic injury and accelerated tumor formation after genotoxic challenge. In the cirrhotic CCl4-induced background, TG221 mice develop fibrosis and cirrhosis followed by dysplastic and malignant lesions, mirroring the natural history of human HCC. Metformin administered during early fibrosis prevented macroscopic tumor formation and suppressed PI3K/AKT/mTOR signaling. Anti-miR-221 and miR-199a-3p mimics reduced tumor burden, restored tumor-suppressive pathways and improved liver integrity, thus indicating feasible chemopreventive strategies. From a therapeutic point of view, miR-199a-3p replacement synergized with palbociclib and overcame sorafenib resistance. A miR-199a-3p-responsive oncolytic adenovirus achieved tumor-selective replication with minimal toxicity. This review highlights the importance of the TG221 transgenic mouse as a powerful model for studying miRNA-driven hepatocarcinogenesis and enables preclinical evaluation of RNA-based chemopreventive and therapeutic approaches. Metformin, miRNA inhibition, miRNA replacement and miRNA-guided viral therapies emerge as promising approaches for advancing precision prevention and treatment strategies in HCC.

Metabolic activation of lumisterol to biologically active metabolites and their mechanism of action.

While miR-22 is a suppressor of hepatocellular carcinoma (HCC), galectin-1 (Gal-1) serves as a HCC biomarker. Our previous studies have shown the effectiveness of miR-22 gene therapy and silencing Gal-1 as two potential novel options in treating HCC in preclinical mouse models. This study examines the significance of the miR-22-Gal-1 axis in HCC development and treatment. The roles of miR-22 and Gal-1 in human HCC were analyzed using the Cancer Genome Atlas database based on their expression levels. The temporal effects of miR-22 were studied by analyzing signaling pathways affected by miR-22 expression levels during HCC progression. AAV8-miR-22, AAV9-Gal-1 siRNA, and LLS30, a Gal-1 inhibitor, were used to treat orthotopic mouse HCC. Spatial transcriptomics established the location-specific effects of miR-22 in mouse HCC. The signaling pathways affected by miR-22 and Gal-1 were identified by analyzing human HCC transcriptomics compared with those found in miR-22, Gal-1 siRNA, or LLS30-treated mouse HCC. In the early stages of HCC, miR-22-high HCC exhibited extensive upregulation of endobiotic metabolism and xenobiotic detoxification signaling, accompanied by the activation of complement and clotting cascades. In late HCC stages, miR-22-high HCC exhibited heightened innate and adaptive immunity, associated with increased interferon signaling. These impacts were primarily observed in the tumors. At the tumor margin, miR-22 inhibited the Rho GTPase and cell-matrix interaction, revealing its role in reducing matrix remodeling and mobility. In non-tumor areas, miR-22 inhibited inflammation by reducing neutrophil degranulation, platelet activation, chemokine receptor binding, and fiber formation. miR-22, Gal-1 silencing, and LLS30 each exhibited anti-HCC effects and targeted common intracellular signaling pathways. Moreover, the anti-HCC effect of miR-22 was dependent on Gal-1 silencing. miR-22-high/Gal-1-low HCC patients had the best survival outcomes. In addition to the above-mentioned key intracellular pathways, miR-22 gene therapy and Gal-1 siRNA treatment of HCC reduced O-linked glycosylation, suggesting the role of the miR-22-Gal-1 axis in modifying glycosylation, which may affect the extracellular functions of Gal-1. In summary, the miR-22-Gal-1 axis can be an HCC prognostic biomarker, and it has vital roles in regulating metabolism and tumor immunity.

Atezolizumab plus bevacizumab (Atez/Bev) is the first-line immunotherapy for advanced hepatocellular carcinoma (HCC), yet many patients show primary or acquired resistance. We aimed to identify tumor-intrinsic mechanisms driving immune cold tumor microenvironments (TMEs) and Atez/Bev resistance. We used a genetically heterogeneous immunocompetent HCC mouse model generated by hydrodynamic injection of a barcoded oncogene library, integrating single-cell RNA sequencing, spatial transcriptomics, and bulk RNA sequencing of human HCC tissues. Retrospective analyses included a multi-institutional registry of 549 Atez/Bev-treated patients and 199 surgically resected HCC patients. External validation used RNA-seq data from 247 patients registered in the IMbrave150 and GO30140 trials. In mice, Atez/Bev eliminated hot tumors, while pre-existing cold tumors with exhausted effector T cells and Tregs predominated later. Barcode analysis revealed enrichment of NFE2L2 (NRF2) in resistant tumors. NRF2 overexpression suppressed immune infiltration and conferred resistance, which was reversed by NRF2 or COX2 inhibition. In human cohorts, both non-responders and patients with acquired resistance exhibited high NRF2/COX2 expression and immune exclusion, confirmed by spatial profiling. High NRF2 activity predicted shorter progression-free survival (PFS), whereas concomitant COX2 inhibitor use correlated with longer PFS. Plasma prostaglandin E2 (PGE 2 ) independently predicted poor response and survival. In IMbrave150/GO30140, NRF2 and prostaglandin pathway activation correlated with Atez/Bev resistance but not sorafenib response, validating a treatment-specific mechanism. Tumor-intrinsic activation of the NRF2-COX2-PGE 2 axis drives immune cold TMEs and mediates Atez/Bev resistance in HCC. Targeting this pathway may enhance efficacy, and plasma PGE 2 represents a non-invasive biomarker for stratification.