The pachysandra alkaloids found in Sarcococca ruscifolia demonstrate notable anti-hepatocellular carcinoma activity. Despite their efficacy, the structural diversity of these compounds remains limited, and their precise antitumor mechanism is still unclear. In pursuit of identifying novel lead compounds with high efficacy and low toxicity for combating hepatocellular carcinoma, twenty-three compounds of C20-ketone pachysandra alkaloid derivatives were designed and synthesized by using 3-dimethylamine pachysandra alkaloids as scaffolds. Subsequent in vitro anticancer activity experiments showed that synthetic pachysandra alkaloids had a stronger effect on HepG2 cells than did their natural counterparts, with low toxicity and high selectivity. The most potent derivative, 6k, had an IC50 value of 0.75 μM, demonstrating 25.7-fold greater anticancer activity than sarcovagine D against HepG2 cells. Through network pharmacology and molecular docking analysis, it was revealed that synthetic pachysandra alkaloids may exert their effects by inhibiting the JAK2/STAT3 pathway, thereby preventing the proliferation of liver cancer cells. Further research through scratch tests, immunofluorescence experiments, and Western blot analysis revealed that compound 6k effectively inhibited the migration of HepG2 cells and induced mitochondria-mediated intrinsic apoptosis of HepG2 cells by regulating the JAK2/STAT3 signaling pathway. The aforementioned results indicate that compound 6k could be developed as a potential candidate for the treatment of hepatocellular carcinoma.

Microwave ablation (MWA) is commonly used to treat hepatocellular carcinoma (HCC), but its effects on normal liver tissue and tumors remain unclear. While MWA causes direct tumor destruction, it also induces inflammatory responses in the surrounding liver tissue, which may influence tumor progression, metastasis, and recurrence. The role of cytokine alterations in this post-ablation inflammatory microenvironment is crucial for understanding how MWA impacts tumor behavior.

This study aims to investigate the impact of post-ablation inflammatory responses on HCC recurrence and metastasis through animal experiments and cytokine profiling, with the goal of identifying potential biomarkers or therapeutic targets.

This study involved 35 male C57BL/6 mice (6-8 weeks old) to establish metastatic and orthotopic cancer models. The effects of normal liver tissue ablation and HCC ablation on tumor metastasis and recurrence were investigated. Cytokine expression changes were assessed using the Proteome Profiler Mouse XL Cytokine Array, and prognostic implications were analyzed using the TCGA database. Multiple group comparisons assessed using the Mann-Whitney U-test. Statistical significance was defined as a two-tailed p-value less than 0.05.

Microwave ablation of normal liver tissue promotes intrahepatic metastasis of HCC. Incomplete ablation of liver tumors accelerates intrahepatic or pulmonary metastasis. Post-ablation, increased expression of MMP-9, OPN, VEGF, CHI3L1, AREG, CXCL2, and IL-1α in the peritumoral region suggests a shift toward a pro-inflammatory and pro-metastatic microenvironment, potentially facilitating tumor cell invasion, angiogenesis, and immune evasion.

HCC recurrence and metastasis following ablation may be driven by cytokine-mediated changes in the tumor microenvironment. Targeting key cytokines such as MMP-9, OPN, and CHI3L1 could provide new strategies for improving post-ablation outcomes and reducing recurrence rates in clinical settings.

Hepatocellular carcinoma (HCC) ranks sixth in incidence and third in mortality among all cancers. Chronic infection by hepatitis B and C viruses are the predominant risk factors for HCC, but other factors related to metabolic disorders including diabetes and obesity are also involved.

Ten male HCC patients with chronic HBV infection were included in this study. Primary HCC tissues were obtained from all study participants following liver resection. Normal tissues that were simultaneously collected served as the controls and were defined as tissue at least 5 cm from the tumor edge. Tissues were subjected to untargeted metabolomics and transcriptome analyses.

We identified 31 and 41 differentially expressed metabolites (DEMs) in positive and negative ion modes, respectively. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed that 15 DEMs were enriched in ABC transporters, nine in purine metabolism, eight in central carbon metabolism in cancer, and seven in biosynthesis of amino acids. Regarding the transcriptome analysis, 1,224 significantly up-regulated and 887 down-regulated RNAs were found. KEGG pathway analysis revealed that the most significantly enriched pathways were metabolic pathways. Integrated analysis showed seven pathways that were highly activated in HCC tissues including PI3K/Akt, ABC transporters, caffeine metabolism, carbon metabolism, biosynthesis of amino acids, arginine biosynthesis, alanine, aspartate, and glutamate metabolism.

Some DEMs could be biomarkers or therapeutic targets for HCC. Moreover, we found that MAGEB2 was significantly elevated in HCC tissues for the first time, and its association with HCC needs to be explored by functional studies.

Hepatocellular carcinoma (HCC) is among the leading causes of cancer-related death worldwide. The primary therapies for HCC are liver transplantation, hepatic tumor excision, radiofrequency ablation, and molecular-targeted medicines. An unfavorable prognosis marks HCC and has limited pharmacological response in therapeutic studies. The tumor immune microenvironment (TME) imposes significant selection pressure on HCC, resulting in its evolution and recurrence after various treatments. As the principal cellular constituents of tumor-infiltrating lymphocytes (TILs), T cells have shown both anti-tumor and protumor actions in HCC. T cell-mediated immune responses are pivotal in cancer monitoring and elimination. TILs are recognized for their critical involvement in the progression, prognosis, and immunotherapeutic management of HCC. Foxp3 + , CD8 + , CD3 + , and CD4 + T cells are the extensively researched subtypes of TILs. This article examines the functions and processes of several subtypes of TILs in HCC. Emerging T cell-based therapies, including TILs and chimeric antigen receptor (CAR)-T cell therapy, have shown tumor regression in several clinical and preclinical studies. Herein, it also delves into the existing T cell-based immunotherapies in HCC, with emphasis on TILs and CAR-T cells.

Liver cancer (LC) poses a significant global health challenge due to its high incidence and poor prognosis. Current systemic treatment options, such as surgery, chemotherapy, radiofrequency ablation, and immunotherapy, have shown limited effectiveness for advanced LC patients. Moreover, owing to the heterogeneous nature of LC, it is crucial to uncover more in-depth pathogenic mechanisms and develop effective treatments to address the limitations of the existing therapeutic modalities. Increasing evidence has revealed the crucial role of the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway in the pathogenesis of LC. The specific mechanisms driving the JAK-STAT pathway activation in LC, participate in a variety of malignant biological processes, including cell differentiation, evasion, anti-apoptosis, immune escape, and treatment resistance. Both preclinical and clinical investigations on the JAK-STAT pathway inhibitors have exhibited potential in LC treatment, thereby opening up avenues for the development of more targeted therapeutic strategies for LC. In this study, we provide an overview of the JAK-STAT pathway, delving into the composition, activation, and dynamic interplay within the pathway. Additionally, we focus on the molecular mechanisms driving the aberrant activation of the JAK-STAT pathway in LC. Furthermore, we summarize the latest advancements in targeting the JAK-STAT pathway for LC treatment. The insights presented in this review aim to underscore the necessity of research into the JAK-STAT signaling pathway as a promising avenue for LC therapy.

JAK/STAT3 is one of the critical signaling pathways involved in the occurrence and development of hepatocellular carcinoma (HCC). BBI608 (Napabucasin), as a novel small molecule inhibitor of STAT3, has shown previously excellent anti-HCC effects in vitro and in mouse models. However, low bioavailability, high cytotoxicity and other shortcomings limit its clinical application. In this study, PLGA was selected to prepare Napabucasin PLGA nanoparticles (NPs) by solvent evaporation method, overcoming these limitations and improving the passive targeting effect that nanoparticle mediated. Base on this, we systematically evaluated the anti-HCC effect of Napabucasin-PLGA NPs and explored the underlying mechanisms.

Napabucasin-PLGA NPs were prepared by solvent evaporation method. CCK-8 assay, Annexin V/PI double staining, RT-qPCR, colony formation assay, and Western blotting were performed to evaluate the anti-HCC effect of Napabucasin-PLGA NPs in vitro. Proliferation assay and migration assay were used to detect the effects of Napabucasin-PLGA NPs-treated HCC-TAMs on tumor biological characteristics of HCC cells. Flow cytometry was used to detect anti-HCC immune responses induced by Napabucasin-PLGA NPs in vivo.

Our results demonstrated that Napabucasin-PLGA NPs could improve the bioavailability of Napabucasin and enhance Napabucasin-mediated the anti-HCC effects in vitro and in vivo with no significant drug toxicity. In addition to the direct inhibitory effects on the tumor biological characteristics of HCC cells, Napabucasin-PLGA NPs could promote the polarization of macrophages from tumor-promoting M2-type to anti-tumor M1-type, improving the tumor immune microenvironment and augmenting T cell-mediated anti-tumor responses. The underlining mechanisms showed Napabucasin-PLGA NPs suppressed the STAT3/FAO signaling axis in HCC-induced tumor-associated macrophages (TAMs).

These findings demonstrated Napabucasin-PLGA NPs is a potential therapeutic candidate for HCC, and provided a new theoretical and experimental basis for further development and clinical application of Napabucasin.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths worldwide, and the development of effective treatment strategies remains a significant challenge in the management of advanced HCC patients. The emergence of tyrosine kinase inhibitors (TKIs) has been a significant advancement in the treatment of HCC, as these targeted therapies have shown promise in prolonging the survival of patients with advanced disease. Although immunotherapy is currently considered as the first line of treatment for advanced HCC patients, many such patients do not meet the clinical criteria to be eligible for immunotherapy, and in many parts of the world there is still lack of accessibility to immunotherapy. As such, TKIs still serve as the first line of treatment and play a major role in the treatment repertoire for advanced HCC patients. However, the development of resistance to these agents is a major obstacle that must be overcome. In this review, we explore the underlying mechanisms of resistance to TKIs in HCC, the clinical implications of this resistance, and the potential strategies to overcome or prevent the emergence of resistance.

Cancer, a multifactorial pathological condition, is primarily caused due to mutations in multiple genes. Hepatocellular carcinoma (HCC) is a form of primary liver cancer that is often diagnosed at the advanced stage. Current treatment strategies for advanced HCC involve systemic therapies which are often hindered due to the emergence of resistance and toxicity. Therefore, a multitarget approach might prove more effective in HCC treatment. The present study focuses on targeting signal transducer and activator of transcription 3 (STAT3), forkhead box class O3a (FOXO3a), and proviral integration site for Moloney murine leukemia virus-1 (Pim-1) kinase, using a Food and Drug Administration (FDA)-approved anticancer drug library. Two compounds, namely, radotinib and capmatinib, were identified as top compounds using molecular docking. Among the two compounds, radotinib exhibited significant binding values towards the targeted proteins and their heterodimers. Furthermore, in vitro experiments involving 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT), live/dead, 4',6-diamidino-2-phenylindole, and clonogenic assays were performed to evaluate the effect of radotinib in human hepatoblastoma cell line/hepatocellular carcinoma cells. The gene expression data indicated reduced expression of FOXO3a and Pim-1, but no basal-level alteration of STAT3. The Western blot analysis assay showed that the phosphorylation level of STAT3 was significantly decreased upon radotinib treatment. Taken together, our findings suggest that radotinib, which is currently used in the treatment of chronic myeloid leukemia (CML), could be considered as a potential candidate for repurposing in the treatment of HCC.

The genesis and progression of tumors are multifaceted processes influenced by genetic mutations within the tumor cells and the dynamic interplay with their surrounding milieu, which incessantly impacts the course of cancer. The tumor microenvironment (TME) is a complex and dynamic entity that encompasses not only the tumor cells but also an array of non-cancerous cells, signaling molecules, and the extracellular matrix. This intricate network is crucial in tumor progression, metastasis, and response to treatments. The TME is populated by diverse cell types, including immune cells, fibroblasts, endothelial cells, alongside cytokines and growth factors, all of which play roles in either suppressing or fostering tumor growth. Grasping the nuances of the interactions within the TME is vital for the advancement of targeted cancer therapies. Consequently, a thorough understanding of the alterations of TME and the identification of upstream regulatory targets have emerged as a research priority. NF-κB transcription factors, central to inflammation and innate immunity, are increasingly recognized for their significant role in cancer onset and progression. This review emphasizes the crucial influence of the NF-κB signaling pathway within the TME, underscoring its roles in the development and advancement of cancer. By examining the interactions between NF-κB and various components of the TME, targeting the NF-κB pathway appears as a promising cancer treatment approach.

Dietary rhythms have emerged as a relevant variable in the equation relating nutrition and health. Both experimental and epidemiological studies point to potential beneficial effects of adequate fasting intervals between meals on the evolution of chronic diseases associated with aging. Metabolic dysfunction-associated steatotic liver disease (MASLD) is eminently related to diet and unsurprisingly, diet-based approaches are a mainstay in countering its long-term clinical evolution, including the emergence of hepatocellular carcinoma (HCC). We briefly discuss current evidence linking fasting intervals, MASLD, and HCC and propose a working hypothesis to reconcile some of the apparently conflicting results. This hypothesis relates the beneficial effects of time-restricted eating schedules to the quantity and quality of food, and it is easily amenable to testing.

Although most hepatocellular carcinoma (HCC) cases are driven by hepatitis and cirrhosis, a subset of patients with chronic hepatitis B develop HCC in the absence of advanced liver disease, indicating the oncogenic potential of hepatitis B virus (HBV). We investigated the role of HBV transcripts and proteins on HCC development in the absence of inflammation in HBV-transgenic mice.

HBV-transgenic mice replicating HBV and expressing all HBV proteins from a single integrated 1.3-fold HBV genome in the presence or absence of wild-type HBx (HBV1.3/HBVxfs) were analyzed. Flow cytometry, molecular, histological and in vitro analyses using human cell lines were performed. Hepatocyte-specific Stat3- and Socs3-knockout was analyzed in HBV1.3 mice.

Approximately 38% of HBV1.3 mice developed liver tumors. Protein expression patterns, histology, and mutational landscape analyses indicated that tumors resembled human HCC. HBV1.3 mice showed no signs of active hepatitis, except STAT3 activation, up to the time point of HCC development. HBV-RNAs covering HBx sequence, 3.5-kb HBV RNA and HBx-protein were detected in HCC tissue. Interestingly, HBVxfs mice expressing all HBV proteins except a C-terminally truncated HBx (without the ability to bind DNA damage binding protein 1) showed reduced signs of DNA damage response and had a significantly reduced HCC incidence. Importantly, intercrossing HBV1.3 mice with a hepatocyte-specific STAT3-knockout abrogated HCC development.

Expression of HBV-proteins is sufficient to cause HCC in the absence of detectable inflammation. This indicates the oncogenic potential of HBV and in particular HBx. In our model, HBV-driven HCC was STAT3 dependent. Our study highlights the immediate oncogenic potential of HBV, challenging the idea of a benign highly replicative phase of HBV infection and indicating the necessity for an HBV 'cure'.

Although most HCC cases in patients with chronic HBV infection occur after a sequence of liver damage and fibrosis, a subset of patients develops HCC without any signs of advanced liver damage. We demonstrate that the expression of all viral transcripts in HBV-transgenic mice suffices to induce HCC development independent of inflammation and fibrosis. These data indicate the direct oncogenic effects of HBV and emphasize the idea of early antiviral treatment in the 'immune-tolerant' phase (HBeAg-positive chronic HBV infection).

With the rapid advancement of optical image diagnostic technology, researchers are delving into the potential applications in the field of cancer diagnosis and treatment. The exact link between the SEZ6L2 gene and cancer immune infiltration remains elusive.

This study aims to investigate the relationship between SEZ6L2 gene overexpression and cancer immune infiltration using optical image diagnostic technology, thereby presenting novel insights for enhancing cancer diagnosis and treatment strategies. Tissue samples obtained from cancer patients were meticulously analyzed to quantitatively assess the expression of the SEZ6L2 gene through light image diagnostic technology. Additionally, immunohistochemical techniques were employed to assess the nature and quantity of immune infiltrating cells within the cancerous tissues.

The enrichment pathways were found to include complement activation, circulating immunoglobulin mediated humoral immune response, protein activation cascade, immunoglobulin complex, and immunoglobulin. In addition, the expression of SEZ6L2 is closely related to the infiltration level of tumor infiltrating immune cells (TIICs), and there is a potential relationship between the expression of SEZ6L2 and different marker genes of TIIC.

Increased SEZ6L2 mRNA expression in breast invasive carcinoma was significantly associated with negative prognosis and immune invasion. SEZ6L2 may be a novel prognostic biomarker and a potential immunotherapeutic target in BRCA.

TNF is a potent cytokine known for its involvement in physiology and pathology. In Rheumatoid Arthritis (RA), persistent TNF signals cause aberrant activation of synovial fibroblasts (SFs), the resident cells crucially involved in the inflammatory and destructive responses of the affected synovial membrane. However, the molecular switches that control the pathogenic activation of SFs remain poorly defined. Cyld is a major component of deubiquitination (DUB) machinery regulating the signaling responses towards survival/inflammation and programmed necrosis that induced by cytokines, growth factors and microbial products. Herein, we follow functional genetic approaches to understand how Cyld affects arthritogenic TNF signaling in SFs. We demonstrate that in spontaneous and induced RA models, SF-Cyld DUB deficiency deteriorates arthritic phenotypes due to increased levels of chemokines, adhesion receptors and bone-degrading enzymes generated by mutant SFs. Mechanistically, Cyld serves to restrict the TNF-induced hyperactivation of SFs by limiting Tak1-mediated signaling, and, therefore, leading to supervised NF-κB and JNK activity. However, Cyld is not critically involved in the regulation of TNF-induced death of SFs. Our results identify SF-Cyld as a regulator of TNF-mediated arthritis and inform the signaling landscape underpinning the SF responses.

Signal transducer and activator of transcription 3 (STAT3) plays an important role in the occurrence and progression of tumors, leading to resistance and poor prognosis. Activation of STAT3 signaling is frequently detected in hepatocellular carcinoma (HCC), but potent and less toxic STAT3 inhibitors have not been discovered. Here, based on antisense technology, we designed a series of stabilized modified antisense oligonucleotides targeting STAT3 mRNA (STAT3 ASOs). Treatment with STAT3 ASOs decreased the STAT3 mRNA and protein levels in HCC cells. STAT3 ASOs significantly inhibited the proliferation, survival, migration, and invasion of cancer cells by specifically perturbing STAT3 signaling. Treatment with STAT3 ASOs decreased the tumor burden in an HCC xenograft model. Moreover, aberrant STAT3 signaling activation is one of multiple signaling pathways involved in sorafenib resistance in HCC. STAT3 ASOs effectively sensitized resistant HCC cell lines to sorafenib in vitro and improved the inhibitory potency of sorafenib in a resistant HCC xenograft model. The developed STAT3 ASOs enrich the tools capable of targeting STAT3 and modulating STAT3 activity, serve as a promising strategy for treating HCC and other STAT3-addicted tumors, and alleviate the acquired resistance to sorafenib in HCC patients. A series of novel STAT3 antisense oligonucleotide were designed and showed potent anti-cancer efficacy in hepatocellular carcinoma in vitro and in vivo by targeting STAT3 signaling. Moreover, the selected STAT3 ASOs enhance sorafenib sensitivity in resistant cell model and xenograft model.

Steatotic liver, characterized by the accumulation of fat in the liver, poses significant health risks including metabolic dysfunction-associated steatotic liver disease (MASLD) and an elevated risk of primary liver cancer. Emerging evidence indicates a robust association between steatotic liver and increased susceptibility to extrahepatic primary cancers and their metastases. The deposition of fat induces dynamic changes in hepatic microenvironments, thereby fostering inflammation and immune responses that enhance liver metastasis from extrahepatic primary cancers. This review explores the impact of steatotic liver on hepatic carcinogenesis and metastasis from extrahepatic cancers, with a specific focus on hepatocyte-derived factors and the immune microenvironment. By emphasizing novel conclusions, this article underscores the timely relevance of understanding these intricate connections.

Chemotherapy is one of the primary and indispensable intervention against cancers though it is always accompanied by severe side effects especially cachexia. Cachexia is a fatal metabolic disorder syndrome, mainly characterized by muscle loss. Oxidative stress is the key factor that trigger cachectic muscle loss by inducing imbalance in protein metabolism and apoptosis. Here, we showed an oral compound (Z526) exhibited potent alleviating effects on C2C12 myotube atrophy induced by various chemotherapeutic agents in vitro as well as mice muscle loss and impaired grip force induced by oxaliplatin in vivo. Furthermore, Z526 also could ameliorate C2C12 myotube atrophy induced by the combination of chemotherapeutic agents with conditioned medium of various tumor cells in vitro as well as mice muscle atrophy of C26 tumor-bearing mice treated with oxaliplatin. The pharmacological effects of Z526 were based on its potency in reducing oxidative stress in cachectic myocytes and muscle tissues, which inhibited the activation of NF-κB and STAT3 to decrease Atrogin-1-mediated protein degradation, activated the AKT/mTOR signaling pathway to promote protein synthesis, regulated Bcl-2/BAX ratio to reduce Caspase-3-triggered apoptosis. Our work suggested Z526 to be an optional strategy for ameliorating cachexia muscle atrophy in the multimodality treatment of cancers.

Hepatocellular carcinoma (HCC) is a common tumor. Our group has previously reported that sorcin (SRI) plays an important role in the progression and prognosis of HCC. This study aims to explore the mechanism of SRI inhibiting the mitochondrial apoptosis. Bioinformatics analysis, co-IP and immunofluorescence were used to analyze the relationship between SRI and STAT3. MMP and Hoechst staining were performed to detect the effect of SRI on cell apoptosis. The expression of apoptosis-related proteins and NF-κB signaling pathway were examined by Western blot and immunohistochemistry when SRI overexpression or underexpression in vivo and in vitro were found. Moreover, inhibitors were used to further explore the molecular mechanism. Overexpression of SRI inhibited cell apoptosis, which was attenuated by SRI knockdown in vitro and in vivo. Moreover, we identified that STAT3 is an SRI-interacting protein. Mechanistically, SRI interacts with STAT3 and then activates the NF-κB signaling pathway in vitro and in vivo. SRI interacting with STAT3 inhibits apoptosis by the NF-κB pathway and further contributes to the proliferation in HCC, which offers a novel clue and a new potential therapeutic target for HCC.

Hepatocyte nuclear factor 4-alpha (HNF4α), a well-preserved member of the nuclear receptor superfamily of transcription factors, is found in the liver. It is recognized as a central controller of gene expression specific to the liver and plays a key role in preserving the liver's homeostasis. Irregular expression of HNF4α is increasingly recognized as a crucial factor in the proliferation, cell death, invasiveness, loss of specialized functions, and metastasis of cancer cells. An increasing number of studies are pointing to abnormal HNF4α expression as a key component of cancer cell invasion, apoptosis, proliferation, dedifferentiation, and metastasis. Understanding HNF4α's intricate involvement in liver carcinogenesis provides a promising avenue for therapeutic intervention. This chapter attempts to shed light on the diverse aspects of HNF4's role in liver carcinogenesis and demonstrate how this knowledge can be harnessed for approaches to prevent and treat liver cancer. This comprehensive chapter will offer an elaborate perspective on HNF4's function in liver cancer, delineating its molecular mechanisms that aid in the emergence of liver cancer. Furthermore, it will highlight the potential to help create more effective and precisely targeted therapeutic strategies, rekindling fresh optimism in the fight against this formidable condition.

Oral cancer stands as a prevalent maligancy worldwide; however, its therapeutic potential is limited by undesired effects and complications. As a medicinal edible fungus, Chaga mushroom (Inonotus obliquus) exhibits anticancer effects across diverse cancers. Yet, the precise mechanisms underlying its efficacy remain unclear. We explored the detailed mechanisms underlying the anticancer action of Chaga mushroom extract in oral cancer cells (HSC-4). Following treatment with Chaga mushroom extracts, we analyzed cell viability, proliferation capacity, glycolysis, mitochondrial respiration, and apoptosis. Our findings revealed that the extract reduced cell viability and proliferation of HSC-4 cells while arresting their cell cycle via suppression of STAT3 activity. Regarding energy metabolism, Chaga mushroom extract inhibited glycolysis and mitochondrial membrane potential in HSC-4 cells, thereby triggering autophagy-mediated apoptotic cell death through activation of the p38 MAPK and NF-κB signaling pathways. Our results indicate that Chaga mushroom extract impedes oral cancer cell progression, by inhibiting cell cycle and proliferation, suppressing cancer cell energy metabolism, and promoting autophagy-mediated apoptotic cell death. These findings suggest that this extract is a promising supplementary medicine for the treatment of patients with oral cancer.

The intestinal microbiome and the gut-liver axis play a major role in health and disease. The human gut harbors trillions of microbes and a disruption of the gut homeostasis can contribute to liver disease. In this review, the progress in the field within the last 3 years is summarized, focusing on metabolic dysfunction-associated steatotic liver disease (MASLD), alcohol-associated liver disease (ALD), autoimmune liver disease (AILD), and hepatocellular carcinoma (HCC).

Changes in the fecal virome and fungal mycobiome have been described in patients with various liver diseases. Several microbial derived metabolites including endogenous ethanol produced by bacteria, have been mechanistically linked to liver disease such as MASLD. Virulence factors encoded by gut bacteria contribute to ALD, AILD and HCC. Novel therapeutic approaches focused on the microbiome including phages, pre- and postbiotics have been successfully used in preclinical models. Fecal microbiota transplantation has been effective in attenuating liver disease. Probiotics are safe in patients with alcohol-associated hepatitis and improve liver disease and alcohol addiction.

The gut-liver axis plays a key role in the pathophysiology of liver diseases. Understanding the microbiota in liver disease can help to develop precise microbiota centered therapies.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. Functionally uncharacterized genes are an attractive repository to explore candidate oncogenes. It is demonstrated that C21orf58 displays an oncogenic role in promoting cell growth, tumorigenesis and sorafenib resistance of HCC cells by abnormal activation of STAT3 signaling. Mechanistically, a novel manner to regulate STAT3 signaling that adaptor C21orf58 forms a ternary complex is reveal with N-terminal domain of STAT3 and SH2 domain of JAK2, by which C21orf58 overactivates wild-type STAT3 by facilitating its phosphorylation mediated by JAK2, and hyper-activates of constitutively mutated STAT3 due to preferred binding with C21orf58 and JAK2. Moreover, it is validated that inhibition of C21orf58 with drug alminoprofen, selected by virtual screening, could effectively repress the viability and tumorigenesis of HCC cells. Therefore, it is identified that C21orf58 functions as an oncogenic adaptor, reveal a novel regulatory mechanism of JAK2/STAT3 signaling, explain the cause of abnormal activity of activated mutants of STAT3, and explore the attractive therapeutic potential by targeting C21orf58 in HCC.

The incidence of hepatocellular carcinoma (HCC) ranks first among primary liver cancers, and its mortality rate exhibits a consistent annual increase. The treatment of HCC has witnessed a significant surge in recent years, with the emergence of targeted immune therapy as an adjunct to early surgical resection. Adoptive cell therapy (ACT) using tumor-infiltrating lymphocytes (TIL) has shown promising results in other types of solid tumors. This article aims to provide a comprehensive overview of the intricate interactions between different types of TILs and their impact on HCC, elucidate strategies for targeting neoantigens through TILs, and address the challenges encountered in TIL therapies along with potential solutions. Furthermore, this article specifically examines the impact of oncogenic signaling pathways activation within the HCC tumor microenvironment on the infiltration dynamics of TILs. Additionally, a concise overview is provided regarding TIL preparation techniques and an update on clinical trials investigating TIL-based immunotherapy in solid tumors.

Physiologically, FoxA1 plays a key role in liver differentiation and development, and pathologically exhibits an oncogenic role in prostate and breast cancers. However, its role and upstream regulation in liver tumorigenesis remain unclear. Here, we demonstrate that FoxA1 acts as a tumor suppressor in liver cancer. Using a CRISPR-based kinome screening approach, noncanonical inflammatory kinase IKBKE has been identified to inhibit FoxA1 transcriptional activity. Notably, IKBKE directly binds to and phosphorylates FoxA1 to reduce its complex formation and DNA interaction, leading to elevated hepatocellular malignancies. Nonphosphorylated mimic Foxa1 knock-in mice markedly delay liver tumorigenesis in hydrodynamic transfection murine models, while phospho-mimic Foxa1 knock-in phenocopy Foxa1 knockout mice to exhibit developmental defects and liver inflammation. Notably, Ikbke knockout delays diethylnitrosamine (DEN)-induced mouse liver tumor development. Together, our findings not only reveal FoxA1 as a bona fide substrate and negative nuclear effector of IKBKE in hepatocellular carcinioma (HCC) but also provide a promising strategy to target IKBEK for HCC therapy.

Lignin, as an abundant aromatic biopolymer in plants, has great potential for medical applications due to its active sites, antioxidant activity, low biotoxicity, and good biocompatibility. In this work, a simple and ecofriendly approach for lignin fractionation and modification was developed to improve the antitumor activity of lignin. The lignin fraction KL-3 obtained by the lignin gradient acid precipitation at pH = 9-13 showed good cytotoxicity. Furthermore, the cell-feeding lignin after additional structural modifications such as demethylation (DKL-3), sulfonation (SL-3), and demethylsulfonation (DSKL-3) could exhibit higher glutathione responsiveness in the tumor microenvironment, resulting in reactive oxygen species accumulation and mitochondrial damage and eventually leading to apoptosis in HepG2 cells with minimal damage to normal cells. The IC50 values for KL-3, SL-3, and DSKL-3 were 0.71, 0.57, and 0.41 mg/mL, respectively, which were superior to those of other biomass extractives or unmodified lignin. Importantly, in vivo experiments conducted in nude mouse models demonstrated good biosafety and effective tumor destruction. This work provides a promising example of constructing carrier-free functionalized lignin antitumor materials with different structures for inhibiting the growth of human hepatocellular carcinoma (HepG2) cells, which is expected to improve cancer therapy outcomes.

Early diabetic retinopathy (DR) is characterized by chronic inflammation, excessive oxidative stress, and retinal microvascular damage. Syringaresinol (SYR), as a natural polyphenolic compound, has been proved to inhibit many disease progression due to its antiinflammatory and antioxidant properties. The present study focuses on exploring the effect of SYR on hyperglycemia-induced early DR as well as the underlying mechanisms.

Wild-type (WT) and nuclear factor erythroid 2-related factor 2 (Nrf2)-knockout C57BL/6 mice of type 1 diabetes and high glucose (HG)-induced RF/6A cells are used as in vivo and in vitro models, respectively. This study finds that SYR protects the retinal structure and function in diabetic mice and reduces the permeability and apoptosis of HG-treated RF/6A cells. Meanwhile, SYR distinctly mitigates inflammation and oxidative stress in vivo and vitro. The retinal microvascular damages are suppressed by SYR via downregulating hypoxia-inducible factor-1α (HIF-1α)/vascular endothelial growth factor (VEGF) pathway. Whereas, SYR-provided protective effects are diminished in Nrf2-knockout mice, indicating that SYR improves DR progression by activating Nrf2. Similarly, SYR cannot exert protective effects against HG-induced oxidative stress and endothelial injury in small interfering RNA (siRNA)-Nrf2-transfected RF/6A cells.

In summary, SYR suppresses oxidative stress via activating Nrf2 antioxidant pathway, which ameliorates retinal microvascular damage by downregulating HIF-1α/VEGF, thereby alleviating early DR progression.

Liver damage caused by various factors results in fibrosis and inflammation, leading to cirrhosis and cancer. Fibrosis results in the accumulation of extracellular matrix components. The role of STAT proteins in mediating liver inflammation and fibrosis has been well documented; however, approved therapies targeting STAT3 inhibition against liver disease are lacking. This study investigated the anti-fibrotic and anti-inflammatory effects of STAT3 decoy oligodeoxynucleotides (ODN) in hepatocytes and liver fibrosis mouse models. STAT3 decoy ODN were delivered into cells using liposomes and hydrodynamic tail vein injection into 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-fed mice in which liver injury was induced. STAT3 target gene expression changes were verified using qPCR and Western blotting. Liver tissue fibrosis and bile duct proliferation were assessed in animal experiments using staining techniques, and macrophage and inflammatory cytokine distribution was verified using immunohistochemistry. STAT3 decoy ODN reduced fibrosis and inflammatory factors in liver cancer cell lines and DDC-induced liver injury mouse model. These results suggest that STAT3 decoy ODN may effectively treat liver fibrosis and must be clinically investigated.

suppression of methylation inhibitors (epigenetic genes) in hepatocarcinogenesis induced by diethylnitrosamine using glycyrrhetinic acid.

In the current work, we investigated the effect of sole GA combined with different agents such as doxorubicin (DOX) or probiotic bacteria (Lactobacillus rhamanosus) against hepatocarcinogenesis induced by diethylnitrosamine to improve efficiency. The genomic DNA was isolated from rats' liver tissues to evaluate either methylation-sensitive or methylation-dependent resection enzymes. The methylation activity of the targeting genes DLC-1, TET-1, NF-kB, and STAT-3 was examined using specific primers and cleaved DNA products. Furthermore, flow cytometry was used to determine the protein expression profiles of DLC-1 and TET-1 in treated rats' liver tissue.

Our results demonstrated the activity of GA to reduce the methylation activity in TET-1 and DLC-1 by 33.6% and 78%, respectively. As compared with the positive control. Furthermore, the association of GA with DOX avoided the methylation activity by 88% and 91% for TET-1 and DLC-1, respectively, as compared with the positive control. Similarly, the combined use of GA with probiotics suppressed the methylation activity in the TET-1 and DLC-1 genes by 75% and 81% for TET-1 and DLC-1, respectively. Also, GA and its combination with bacteria attenuated the adverse effect in hepatocarcinogenesis rats by altering potential methylomic genes such as NF-kb and STAT3 genes by 76% and 83%, respectively.

GA has an ameliorative effect against methylation inhibitors in hepatocellular carcinoma (HCC) by decreasing the methylation activity genes.

Nonalcoholic fatty liver disease (NAFLD) is prevalent in the majority of individuals with obesity, but in a subset of these individuals, it progresses to nonalcoholic steatohepatitis (0NASH) and fibrosis. The mechanisms that prevent NASH and fibrosis in the majority of patients with NAFLD remain unclear. Here, we report that NAD(P)H oxidase 4 (NOX4) and nuclear factor erythroid 2-related factor 2 (NFE2L2) were elevated in hepatocytes early in disease progression to prevent NASH and fibrosis. Mitochondria-derived ROS activated NFE2L2 to induce the expression of NOX4, which in turn generated H2O2 to exacerbate the NFE2L2 antioxidant defense response. The deletion or inhibition of NOX4 in hepatocytes decreased ROS and attenuated antioxidant defense to promote mitochondrial oxidative stress, damage proteins and lipids, diminish insulin signaling, and promote cell death upon oxidant challenge. Hepatocyte NOX4 deletion in high-fat diet-fed obese mice, which otherwise develop steatosis, but not NASH, resulted in hepatic oxidative damage, inflammation, and T cell recruitment to drive NASH and fibrosis, whereas NOX4 overexpression tempered the development of NASH and fibrosis in mice fed a NASH-promoting diet. Thus, mitochondria- and NOX4-derived ROS function in concert to drive a NFE2L2 antioxidant defense response to attenuate oxidative liver damage and progression to NASH and fibrosis in obesity.

The oncogene Melanoma differentiation associated gene-9/syndecan binding protein (MDA-9/SDCBP) is overexpressed in many cancers, promoting aggressive, metastatic disease. However, the role of MDA-9 in regulating hepatocellular carcinoma (HCC) has not been well studied.

To unravel the function of MDA-9 in HCC, we generated and characterized a transgenic mouse with hepatocyte-specific overexpression of MDA-9 (Alb/MDA-9). Compared with wild-type (WT) littermates, Alb/MDA-9 mice demonstrated significantly higher incidence of N-nitrosodiethylamine/phenobarbital-induced HCC, with marked activation and infiltration of macrophages. RNA sequencing (RNA-seq) in naive WT and Alb/MDA-9 hepatocytes identified activation of signaling pathways associated with invasion, angiogenesis, and inflammation, especially NF-κB and integrin-linked kinase signaling pathways. In nonparenchymal cells purified from naive livers, single-cell RNA-seq showed activation of Kupffer cells and macrophages in Alb/MDA-9 mice versus WT mice. A robust increase in the expression of Secreted phosphoprotein 1 (Spp1/osteopontin) was observed upon overexpression of MDA-9. Inhibition of NF-κB pathway blocked MDA-9-induced Spp1 induction, and knock down of Spp1 resulted in inhibition of MDA-9-induced macrophage migration, as well as angiogenesis.

Alb/MDA-9 is a mouse model with MDA-9 overexpression in any tissue type. Our findings unravel an HCC-promoting role of MDA-9 mediated by NF-κB and Spp1 and support the rationale of using MDA-9 inhibitors as a potential treatment for aggressive HCC.

Under chronic stress, cells must balance competing demands between cellular survival and tissue function. In metabolic dysfunction-associated steatotic liver disease (MASLD, formerly NAFLD/NASH), hepatocytes cooperate with structural and immune cells to perform crucial metabolic, synthetic, and detoxification functions despite nutrient imbalances. While prior work has emphasized stress-induced drivers of cell death, the dynamic adaptations of surviving cells and their functional repercussions remain unclear. Namely, we do not know which pathways and programs define cellular responses, what regulatory factors mediate (mal)adaptations, and how this aberrant activity connects to tissue-scale dysfunction and long-term disease outcomes. Here, by applying longitudinal single-cell multi -omics to a mouse model of chronic metabolic stress and extending to human cohorts, we show that stress drives survival-linked tradeoffs and metabolic rewiring, manifesting as shifts towards development-associated states in non-transformed hepatocytes with accompanying decreases in their professional functionality. Diet-induced adaptations occur significantly prior to tumorigenesis but parallel tumorigenesis-induced phenotypes and predict worsened human cancer survival. Through the development of a multi -omic computational gene regulatory inference framework and human in vitro and mouse in vivo genetic perturbations, we validate transcriptional (RELB, SOX4) and metabolic (HMGCS2) mediators that co-regulate and couple the balance between developmental state and hepatocyte functional identity programming. Our work defines cellular features of liver adaptation to chronic stress as well as their links to long-term disease outcomes and cancer hallmarks, unifying diverse axes of cellular dysfunction around core causal mechanisms.

Obesity-related complications such as non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes (T2D) are well-established risk factors for the development of hepatocellular carcinoma (HCC). This review provides insights into the molecular mechanisms that underlie the role of steatosis, hyperinsulinemia and hepatic inflammation in HCC development and progression. We focus on recent findings linking intracellular pathways and transcription factors that can trigger the reprogramming of hepatic cells. In addition, we highlight the role of enzymes in dysregulated metabolic activity and consequent dysfunctional signalling. Finally, we discuss the potential uses and challenges of novel therapeutic strategies to prevent and treat NAFLD/T2D-associated HCC.

Unresolved inflammation is a pathological consequence of persistent inflammatory stimulus and perturbation in regulatory mechanisms. It increases the risk of tumour development and orchestrates all stages of tumorigenesis in selected organs. In certain cancers, inflammatory processes create the appropriate conditions for neoplastic transformation. While in other types, oncogenic changes pave the way for an inflammatory microenvironment that leads to tumour development. Of interest, hallmarks of tumour-promoting and cancer-associated inflammation are striking similar, sharing a complex network of stromal (fibroblasts and vascular cells) and inflammatory immune cells that collectively form the tumour microenvironment (TME). The cross-talks of signalling pathways initially developed to support homeostasis, change their role, and promote atypical proliferation, survival, angiogenesis, and subversion of adaptive immunity in TME. These transcriptional and regulatory pathways invariably contribute to cancer-promoting inflammation in chronic inflammatory disorders and foster "smouldering" inflammation in the microenvironment of various tumour types. Besides identifying common target sites of numerous cancer types, signalling programs and their cross-talks governing immune cells' plasticity and functional diversity can be used to develop new fate-mapping and lineage-tracing mechanisms. Here, we review the vital molecular mechanisms and pathways that establish the connection between inflammation and tumour development, progression, and metastasis. We also discussed the cross-talks between signalling pathways and devised strategies focusing on these interaction mechanisms to harness synthetic lethal drug combinations for targeted cancer therapy.

Hepatocellular carcinoma (HCC) is one of the most fatal and fastest growing malignancies. Recently, nonalcoholic steatohepatitis (NASH), characterized by liver steatosis, inflammation, cell injury (hepatocyte ballooning), and different stages of fibrosis, has emerged as a major catalyst for HCC. Because the STE20-type kinases, MST3 and MST4, have been described as critical molecular regulators of NASH pathophysiology, we here focused on determining the relevance of these proteins in human HCC. By analyzing public datasets and in-house cohorts, we found that hepatic MST3 and MST4 expression was positively correlated with the incidence and severity of HCC. We also found that the silencing of both MST3 and MST4, but also either of them individually, markedly suppressed the tumorigenesis of human HCC cells including attenuated proliferation, migration, invasion, and epithelial-mesenchymal transition. Mechanistic investigations revealed lower activation of STAT3 signaling in MST3/MST4-deficient hepatocytes and identified GOLGA2 and STRIPAK complex as the binding partners of both MST3 and MST4. These findings reveal that MST3 and MST4 play a critical role in promoting the progression of HCC and suggest that targeting these kinases may provide a novel strategy for the treatment of liver cancer.