The progression from hepatitis to liver fibrosis (LF) and ultimately to hepatic carcinoma (HCC) represents the advanced stages of various liver diseases. Currently, no universal treatment effectively addresses all three conditions. The Traditional Chinese Medicine formula Xiao-Chai-Hu decoction (XCHD) has shown promise in treating hepatitis, inhibiting LF, and serving as an adjunct therapy for HCC. This study evaluates the efficacy and optimal treatment durations of XCHD in managing these liver diseases using meta-analysis and machine learning techniques.

Registered in the PROSPERO database (CRD42024534445), this meta-analysis systematically searched seven databases, including 54 studies with a total of 5,710 patients. Statistical analysis was performed using Stata 17.0. Five machine learning models-Random Forest (RF), XGBoost, Lasso, Multilayer Perceptron (MLP), and a stacking model combining these algorithms-were employed to analyze the data and predict the time-effect relationships. The optimal durations of XCHD treatment for the liver disease trilogy were subsequently projected.

XCHD significantly improved the primary outcome indicators for hepatitis, liver fibrosis, and HCC. Additionally, XCHD demonstrated a beneficial effect on liver dysfunction caused by these diseases. Machine learning predicted the optimal treatment durations of XCHD as 12 weeks for hepatitis, 20.31 weeks for liver fibrosis, and 12 weeks for HCC.

XCHD is effective in treating the liver disease trilogy, with optimal treatment durations of 12 weeks for hepatitis and HCC, and 20.31 weeks for liver fibrosis. These findings support the potential of XCHD in developing precise clinical strategies for managing liver diseases. This study innovatively integrates meta-analysis with machine learning to determine the optimal treatment durations, providing a novel approach for evidence-based precision medicine in Traditional Chinese Medicine.

Tendinopathy is a chronic, degenerative disease that has increased prevalence in aged populations, and is characterized by a loss in extracellular matrix (ECM) integrity. Recent work has clearly demonstrated age-related deficits in ECM synthesis with aging, as well as some changes to metabolic activity. Since glucose metabolism is critical to protein synthesis and known to be altered in aging, we sought to investigate if age-related changes in metabolism are linked to changes in ECM remodeling. We used our previously developed flexor tendon explant model to expose young and aged tendon explants to various concentrations of glucose and glutamine supplementation and observe changes in metabolic activity, matrix composition, matrix biosynthesis, and expression of metabolic and ECM genes. We hypothesized that elevated levels of glucose and glutamine would lead to increased ECM remodeling as well as elevated gene expression of their respective pathways in young tendons, with no such effect in aged tendons. Interestingly, we found that glutamine processing is affected by glucose levels with increased expression of key glutamine processing pathways with increased glucose, but this effect was lost with aging. We also observed that ECM remodeling is directly related to both glucose and glutamine processing with altered glycosaminoglycan and collagen synthesis with glucose and glutamine media concentration. Overall, our work reveals that glucose and glutamine are intricately linked for both tenocyte health and ECM homeostasis and that their metabolism could be one of the key drivers of age-related deficiencies in tissue maintenance.

Current nanoparticle-based drug delivery systems for tumor therapy face significant challenges in intratumoral penetration and cellular internalization, leading to poor therapeutic efficacy. Herein, it is demonstrated that the sequential integration of glucose oxidase (GOx), catalase (CAT), and urease (URE) onto the half surface of biotin-modified Janus nanoparticles via the chemical coupling way produces nanorobots of multifunctionality and synergistic effect (denoted as UCGPJNRs). They can autonomously and powerfully move in tumor microenvironment (TME) by using endogenous urea as a fuel, enabling to penetrate deeper than 0.55 mm into tumor tissues, ≈5.5-fold of the previous counterparts. The UCGPJNRs perform motion-enhanced biotin receptor-mediated endocytosis and endoplasmic reticulum/Golgi apparatus pathway-mediated exocytosis, greatly improving the internalization efficiency of tumor cells. They release NH3 when moving to produce selective toxicity against tumor cells in hypoxic TME. Further, they enhance the glucose consumption by ≈three times due to the motion-accelerated GOx/CAT cascade reaction, disrupting the metabolism against tumor cells on a large area. After intratumorally injecting into tumor-bearing mice, UCGPJNRs can significantly amplify the in vivo tumor growth inhibition rate through their synergistic effect. This work provides a plausible strategy to overcome current limitations in tumor treatment by anchoring multiple bioenzymes on one nanoparticle.

DDX11 antisense RNA 1 (DDX11-AS1) has been recognized for its strong correlation with hepatocellular carcinoma (HCC). Nevertheless, the exact biological functions and fundamental molecular processes of DDX11-AS1 in HCC require further in-depth investigation.

A comprehensive bioinformatics analysis was carried out to explore the expression of DDX11-AS1 and its clinical implication in HCC utilizing the TCGA data. qRT-PCR was employed to validate the expression of DDX11-AS1 in HCC tissues/cell lines. RNA fluorescence in situ hybridization (RNA-FISH) was used to observe the subcellular localization of DDX11-AS1 in HCC cells. Loss-of-function experiments, both in vitro and in vivo, were executed to elucidate the biological functions of DDX11-AS1 in HCC. RNA sequencing (RNA-seq) was employed to identify genes and signaling pathways potentially regulated by DDX11-AS1. Rescue experiments were conducted to validate that carbonic anhydrase IX (CA9) mediates DDX11-AS1 promoting HCC progression. The influence of nuclear respiratory factor 1 (NRF1) on the transcription of DDX11-AS1 was investigated through dual-luciferase reporter assays and ChIP-qPCR.

The increased expression of DDX11-AS1 is positively associated with several aggressive clinical characteristics (pathologic T stage, histologic grade, AFP level, and vascular invasion), and is closely linked to unfavorable outcomes in HCC patients, acting as a separate hazardous factor for overall survival. DDX11-AS1 is predominantly situated in the nucleus of HCC cells. DDX11-AS1 knockdown impeded the growth, migration, and invasion capabilities of HCC cells in vitro, and reduced the tumor enlargement in a subcutaneous mouse model. RNA-Seq unveiled that silencing DDX11-AS1 lessened the expression of CA9 and suppressed the activity of the MEK/ERK signaling cascade in HCC cells. Rescue experiments uncovered that CA9 acts as a downstream target facilitating the cancer-causing roles of DDX11-AS1 in HCC. Furthermore, DDX11-AS1 was revealed to be transcriptionally regulated by NRF1.

DDX11-AS1, a NRF1-induced lncRNA, facilitates HCC development by upregulating CA9 expression and activating the MEK/ERK signaling cascade.

Hepatocellular carcinoma (HCC) is one of the most fatal malignancies worldwide. Patients are often diagnosed at advanced stages and have short overall survivals. Thus, there is an urgent need to understand the underlying mechanism of HCC development and discover new drug targets. In the present study, an ultrahigh performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS)-based approach was used to investigate the proteome and phosphoproteome alterations between tumour and non-tumour tissues of HCC patients. In total, 678 proteins and 350 phosphoproteins were significantly changed between the two groups. Kyoto encyclopedia of genes and genomes (KEGG) pathway analysis revealed that glycolysis/glucogenesis was one of the most significantly enriched pathways of down-regulated phosphoproteins and PCK2 was one hub protein in this pathway. Furthermore, the phosphosite of the Ser304 residue in PCK2 is highly evolutionarily conserved among different species and is located near to the GDP, Mn2+ binding sites and kinase activity site, which indicate that the phosphorylation of Ser304 may regulate PCK2 activity. HepG2 cell proliferation, invasion and migration were significantly increased when treated with 3-mercaptopicolinic acid, an inhibitor of PCK2, which demonstrated the tumour suppressive activity of PCK2 in HCC. In addition, the low mRNA expression of PCK2 was correlated with poor overall survival of live cancer patients. Overall, our proteomic and phosphoproteomic study revealed the tumour suppressive function of PCK2 in HCC and indicated that activation of its expression or activity may be a potential therapeutic strategy for HCC treatment.

Difenoconazole is a widely used agricultural fungicide that has been frequently detected in aquatic environments. Given its stable presence in aquatic environments, long-term exposure of wild fish may pose a risk to offspring embryonic development. This study demonstrated that exposure of zebrafish to environmental concentrations of difenoconazole throughout their life cycle resulted in abnormal development of offspring embryos/larvae, including decreased heart rate, delayed hatching, increased malformation rate, shortened body length, and increased mortality. These changes were significantly correlated with the affected apoptosis, autophagy, energy metabolism and MAPK signaling pathways in F1 generation. This transgenerational toxic effect results from epigenetic alterations in gametes, impaired nutrient supply from the ovum, and maternal transfer of difenoconazole. After exposure to difenoconazole, the development of female fish offspring was affected more than that of male fish offspring, which was mainly caused by the impaired nutrient supply from the ovum and the maternal transfer of difenoconazole. Because this transgenerational developmental toxicity was observed at environmental levels, difenoconazole may pose a threat to the survival of wild larvae and therefore a risk to wild fish populations.

Endometritis in dairy cows significantly impacts their reproductive performance. However, its underlying mechanisms remain unclear. Hydroxyacyl-CoA dehydrogenase trifunctional multienzyme complex subunit-alpha (HADHA) is known to regulate the occurrence of various diseases, but its role in bovine endometritis is poorly understood. In the present study, an in vitro bovine endometrial epithelial cells (BEECs) inflammation model was constructed to explore the effects of HADHA on inflammation, proliferation, and apoptosis. Functional analyses based on HADHA interference and overexpression revealed that it positively regulated the expression of IL-6, IL-8, and IL-1β in lipopolysaccharide (LPS)-induced BEECs, enhancing reactive oxygen species (ROS) production and promoting inflammation. Concurrently, HADHA decreased the expression of PCNA, CDK2, and CDK4, inhibited mitotic transition of BEECs from S to G2 phase, and negatively regulated BEEC proliferation. It also increased BAX and Caspase-3 expression while decreasing BCL2 expression, hence promoting BEECs apoptosis. Transcriptomic and metabolomic analyses indicated that HADHA modulated inflammation in BEECs by affecting pathways such as the TGF-beta signaling pathway, fatty acid metabolism, and p53 signaling. These findings provide novel insights into HADHA's role in bovine endometritis and reveal future research directions on its regulatory mechanisms.

Ferroptosis, a form of cell death discovered in recent years, is expected to provide new targets for the diagnosis and treatment of hepatocellular carcinoma (HCC) through further research.

Based on data from The Cancer Genome Atlas (TCGA), we screened HCC-associated genes from 259 candidate genes in the FerrDb database. The screened genes were subjected to differential expression analysis, survival analysis, correlation analysis with clinical data, and univariate and multivariate Cox regression analysis. The results were validated with the Gene Expression Profiling Interactive Analysis 2 (GEPIA2) database and the Human Protein Atlas (HPA) database, and signaling pathways were analyzed with the Gene Set Enrichment Analysis (GSEA) enrichment analysis. Human normal hepatocytes and different liver cancer cell lines were used to verify the expression levels of genes, using quantitative reverse transcription PCR (RT-qPCR).

Eight ferroptosis-related genes were finally selected, including ACSL3, ASNS, CHMP5, MYB, PCK2, PGD, SLC38A1, and YY1AP1. The expression of eight genes except PCK2 was significantly correlated with a lower survival rate of HCC, and the expression of PCK2 showed a correlation with a higher survival rate of HCC. The expression of all eight genes was also correlated with clinical traits. GSEA enrichment analysis obtained many pathways such as apoptosis, endocytosis, pathways in cancer, Wnt signaling pathway, primary bile acid biosynthesis, and fatty acid metabolism pathway.

The ACSL3, ASNS, CHMP5, MYB, PCK2, PGD, SLC38A1, and YY1AP1 genes may become markers and new targets for early diagnosis and prognostic assessment of HCC.

Liver cancer, a highly aggressive malignancy, continues to present significant challenges in therapeutic management due to its pronounced chemoresistance. This resistance, which undermines the efficacy of conventional chemotherapy and targeted therapies, is driven by multifaceted mechanisms, with increasing emphasis placed on the protective role of the tumor microenvironment (TME). The hepatocellular carcinoma extracellular matrix (ECM), a primary non-cellular component of the TME, has emerged as a critical regulator in cancer progression and drug resistance, particularly in hepatocellular carcinoma cell (HCC). In this study, a hybrid biomimetic hydrogel was engineered by integrating decellularized hepatocellular carcinoma matrix (DHCM) with gelatin methacrylate (GelMA) precursors. This composite DHCM/GelMA hydrogel was designed to replicate the physicochemical and functional properties of the hepatocellular carcinoma ECM, thereby offering a biomimetic platform to explore the interactions between HCCs and their microenvironment. Leveraging a custom-designed microfluidic 3D printing platform, we achieved high-throughput fabrication of HCC-encapsulated DHCM/GelMA microgels, characterized by enhanced uniformity, biocompatibility, and scalability. These microgels facilitated the construction of hepatocellular carcinoma microtissues, which were subsequently employed for chemoresistance studies. Our findings revealed that DHCM/GelMA microgels closely mimic the hepatocellular carcinoma tumor microenvironment, effectively recapitulating key features of ECM-mediated drug resistance. Mechanistic studies further demonstrated that DHCM significantly upregulates the expression of Aquaporin 3 (AQP3) in the encapsulated HCCs. This upregulation potentially activates mTOR signaling-associated autophagy pathways, thereby enhancing chemoresistance in HCCs. These biomimetic models provide a robust and versatile platform for studying the underlying mechanisms of drug resistance and evaluating therapeutic interventions. This innovative approach highlights the potential of DHCM/GelMA microgels as a transformative tool in cancer-associated tissue engineering and anticancer drug screening. By enabling detailed investigations into the role of ECM in chemoresistance, this study contributes to advancing therapeutic research and offers promising strategies to overcome drug resistance, ultimately improving clinical outcomes in liver cancer treatment.

Cardiac arrest (CA) is a critical medical emergency that can occur in both patients with preexisting conditions and otherwise healthy individuals. Despite successful resuscitation through cardiopulmonary resuscitation (CPR), many survivors are at significant risk of developing post-cardiac arrest syndrome (PCAS), a complex systemic response to CA that includes brain injury as a major component. Phosphoenolpyruvate carboxykinase 1 (PCK1), the first rate-limiting enzyme in gluconeogenesis, has been implicated in various diseases. However, its role in neuronal damage following CA/CPR remains unclear. To investigate the role of PCK1 in neuronal damage after CA/CPR, we established the CA/CPR animal model and hypoxia/re‑oxygenation (H/R) cell model, manipulated PCK1 expression both in vivo and in vitro. We found increased expression of PCK1 in cortical neurons after CA/CPR. In vivo PCK1 overexpression exacerbated brain injury after CA/CPR via augmenting neuroinflammation and neuronal apoptosis. RNA-sequencing suggested PCK1-OE disturbed the neuronal metabolism while immunoprecipitation/mass spectrometry (IP/MS) revealed that PCK1 contributed to the mitochondrial dysfunction via binding to Voltage-dependent anion-selective channel 1 (VDAC1) and promoting its oligomerization and cytochrome c release. Besides, we confirmed that 3-Mercaptopicolinic acid (3-MPA), the PCK1 inhibitor, could ameliorate the mitochondrial dysfunction and apoptosis of neurons both in vitro and in vivo. For the first time, we identified the detrimental role of PCK1 in post-CA brain injury. During CA/CPR, excessive PCK1 binds to VDAC1, promoting its oligomerization and cytochrome c release which leading to neuronal apoptosis and eventually PCAS. Utilization of 3-MPA during CPR could effectively improve the survival rate and prognosis of mice after CA, which may provide a novel strategy for CA/CPR treatment.

Hepatocellular carcinoma (HCC) is a significant global health issue, ranking as the sixth most prevalent malignancy and the fourth leading cause of cancer-related mortality worldwide. Despite advancements in therapeutic strategies, mortality rates for HCC remain high. The tumor immune microenvironment (TIME) plays a vital role in HCC progression by influencing tumor cell survival and growth. Recent studies highlight the essential role of exosomes in mediating intercellular communication within the TIME, particularly in interactions among tumor cells, immune cells, and fibroblasts. These interactions drive critical aspects of tumor development, including immune escape, angiogenesis, drug resistance, and metastasis. A detailed understanding of the molecular mechanisms by which exosomes modulate the TIME is essential for developing targeted therapies. This review systematically evaluated the roles and regulatory mechanisms of exosomes within the TIME of HCC, examining the impact of both HCC-derived and non-HCC-derived exosomes on various cellular components within the TIME. It emphasized their regulatory effects on cell phenotypes and functions, as well as their roles in HCC progression. The review also explored the potential applications of exosome-based immunotherapies, offering new insights into improving therapeutic strategies for HCC.

Primary liver cancer is a common malignant tumor of the digestive system, with hepatocellular carcinoma (HCC) being the most prevalent type. It is characterized by high malignancy, insidious onset, and a lack of specific early diagnostic and therapeutic markers, posing a serious threat to human health. The occurrence and development of HCC are closely related to its metabolic processes. Similar to other malignant tumors, metabolic reprogramming occurs extensively in tumor cells, with glucose metabolism reprogramming being particularly prominent. This is characterized by abnormal activation of glycolysis and inhibition of oxidative phosphorylation and gluconeogenesis, among other changes. Glucose metabolism reprogramming provides intermediates and energy for HCC to meet its demands for rapid growth, proliferation, and metastasis. Additionally, various enzymes and signaling molecules involved in glucose metabolism reprogramming play irreplaceable roles. Therefore, regulating key metabolic enzymes and pathways in these processes is considered an important target for the diagnosis and treatment of HCC. This paper reviews the current status and progress of glucose metabolism reprogramming in HCC, aiming to provide new insights for the diagnosis, detection, and comprehensive treatment strategies of HCC involving combined glucose metabolism intervention in clinical settings.

In this review, we explore the application of next-generation sequencing in liver cancer research, highlighting its potential in modern oncology. Liver cancer, particularly hepatocellular carcinoma, is driven by a complex interplay of genetic, epigenetic, and environmental factors. Key genetic alterations, such as mutations in TERT, TP53, and CTNNB1, alongside epigenetic modifications such as DNA methylation and histone remodeling, disrupt regulatory pathways and promote tumorigenesis. Environmental factors, including viral infections, alcohol consumption, and metabolic disorders such as nonalcoholic fatty liver disease, enhance hepatocarcinogenesis. The tumor microenvironment plays a pivotal role in liver cancer progression and therapy resistance, with immune cell infiltration, fibrosis, and angiogenesis supporting cancer cell survival. Advances in immune checkpoint inhibitors and chimeric antigen receptor T-cell therapies have shown potential, but the unique immunosuppressive milieu in liver cancer presents challenges. Dysregulation in pathways such as Wnt/β-catenin underscores the need for targeted therapeutic strategies. Next-generation sequencing is accelerating the identification of genetic and epigenetic alterations, enabling more precise diagnosis and personalized treatment plans. A deeper understanding of these molecular mechanisms is essential for advancing early detection and developing effective therapies against liver cancer.

Hepatocellular carcinoma (HCC) accounts for over 80% of primary liver cancers and is the third leading cause of cancer-related deaths worldwide. Hepatitis B virus (HBV) infection is the primary etiological factor. Disulfidptosis is a newly discovered form of regulated cell death. This study aims to develop a novel HBV-HCC prognostic signature related to disulfidptosis and explore potential therapeutic approaches through risk stratification based on disulfidptosis.

Transcriptomic data from HBV-HCC patients were analyzed to identify BHDRGs. A prognostic model was established and validated using machine learning, with internal datasets and external datasets for verification. We then performed immune cell infiltration analysis, tumor microenvironment (TME) analysis, and immunotherapy-related analysis based on the prognostic signature. Besides, RT-qPCR and immunohistochemistry were conducted.

A prognostic model was constructed using five genes (DLAT, STC2, POF1B, S100A9, and CPS1). A corresponding prognostic nomogram was developed based on riskScores, age, stage. Stratification by median risk score revealed a significant correlation between the prognostic signature and TME, tumor immune cell infiltration, immunotherapy efficacy, and drug sensitivity. The results of the experiments indicate that DLAT expression is higher in tumor tissues compared to adjacent tissues. DLAT expression is higher in HBV-HCC tumor tissues compared to normal tissues.

This study stratifies HBV-HCC patients into distinct subgroups based on BHDRGs, establishing a prognostic model with significant implications for prognosis assessment, TME remodeling, and personalized therapy in HBV-HCC patients.

Liver cancer, namely hepatocellular carcinoma (HCC), is a major global health concern deeply influenced by environmental factors. Air pollutants emerged as significant contributors to its incidence. This review explores the association between air pollution-specifically particulate matter (PM2.5), industrial chemicals like vinyl chloride, and benzene-and the increased risk of liver cancer. Mechanistically, air pollutants may cause liver damage by inducing oxidative stress, inflammation, and genetic mutations, contributing to cancer development. Epidemiological evidence from cohort and geographic studies highlights a positive correlation between long-term exposure to air pollutants and elevated incidence and mortality of liver cancer. Furthermore, air pollution has been shown to worsen survival outcomes in liver cancer patients, particularly those diagnosed at early stages. The review emphasizes the need for stricter air quality regulations and relevant research for underlying mechanisms exposed to air pollution. Addressing air pollution exposure could be crucial for reducing liver cancer risks and improving public health outcomes.

Edwardsiella piscicida-induced lethal enteritis is a major threat to the sustainable development of seahorse aquaculture. The roles of Carbohydrate-Active enzymes (CAZymes) in interactions between the pathogen and the host are poorly understood. In this study, we found that 22 key CAZymes encoded by E. piscicida might involve in the coordination of five key stages of infection. Specifically, during the motility, adherence, and invasion stages, 10 CAZymes, including CE4, PL8, and CBM48, may significantly increase the activities of Lipid metabolism-associated pathways of the intestinal microbiota (P < 0.01), facilitating pathogen invasion of the host intestinal epithelium. During the replication stage, 11 CAZymes, including GH20, GT4, and GH3, may significantly increase activities of pathways associated with Carbohydrate metabolism (P < 0.01) to promote replication and proliferation of the pathogen. And for avoiding host defenses, GH2 and GH1 may enhance activities of both Carbohydrate and Amino acid metabolic pathways (P < 0.01), facilitating infection and immune evasion. Conjoint analysis showed that E. piscicida might mainly rely on Carbohydrate metabolism for infection, while the host might activate Amino acid metabolic pathways for self-defense. In addition, expressions of 10 key genes, Aldh9a1b, Aoc1, Tpi1b, PCK1, Ldha, Me1, Gla, Cel.2, Ugdh, and Mao, were significantly altered (P < 0.01) and may be used for characterizing host responses to E. piscicida infection. Activities of both Glycolysis/Gluconeogenesis and Tryptophan metabolism were found oppositely changed (P < 0.01) between pathogen and host, respectively, representing the primary focuses of the competition. Overall, this study provides new insights into E. piscicida-mediated intestinal enteritis in fish for the first time from the perspective of CAZymes, as well as a theoretical reference for the prevention and control of these diseases in the aquaculture of seahorses and other fish.

Tendinopathy is an age-associated degenerative disease characterized by a loss in extracellular matrix (ECM). Since glucose and glutamine metabolism is critical to amino acid synthesis and known to be altered in aging, we sought to investigate if age-related changes in metabolism are linked to changes in ECM remodeling. We exposed young and aged tendon explants to various concentrations of glucose and glutamine to observe changes in metabolic processing (enzyme levels, gene expression, etc.) and matrix biosynthesis. Interestingly, we found that glutamine processing is affected by glucose levels, but this effect was lost with aging. ECM synthesis was altered in a protein-dependent manner by increased glucose and glutamine levels in young tendons. However, these changes were not conserved in aged tendons. Overall, our work suggests that glucose and glutamine metabolism is important for ECM homeostasis, and age-related changes in nutrient metabolism could be a key driver of tendon degeneration.

The incidence and mortality rates of hepatocellular carcinoma among Hispanic individuals in the United States are much higher than in non-Hispanic White people. We conducted multi-omics analyses to elucidate molecular alterations in hepatocellular carcinoma among Hispanic patients.

Paired tumor and adjacent nontumor samples were collected from 31 Hispanic hepatocellular carcinomas in South Texas for genomic, transcriptomic, proteomic, and metabolomic profiling. Serum lipids were profiled in 40 Hispanic and non-Hispanic patients with or without clinically diagnosed hepatocellular carcinoma.

Exome sequencing revealed high mutation frequencies of AXIN2 and CTNNB1 in South Texas Hispanic hepatocellular carcinoma patients, suggesting a predominant activation of the Wnt/β-catenin pathway. TERT promoter mutations were also statistically significantly more frequent in the Hispanic cohort (Fisher exact test, P < .05). Cell cycles and liver function were positively and negatively enriched, respectively, with gene set enrichment analysis. Gene sets representing specific liver metabolic pathways were associated with dysregulation of corresponding metabolites. Negative enrichment of liver adipogenesis and lipid metabolism corroborated with a significant reduction in most lipids in serum samples of hepatocellular carcinoma patients (paired t test, P < .0001). Two hepatocellular carcinoma subtypes from our Hispanic cohort were identified and validated with the Cancer Genome Atlas liver cancer cohort. Patients with better overall survival showed higher activity of immune and angiogenesis signatures and lower activity of liver function-related gene signatures. They also had higher levels of immune checkpoint and immune exhaustion markers.

Our study revealed specific molecular features of Hispanic hepatocellular carcinoma and potential biomarkers for therapeutic management. It provides a unique resource for studying Hispanic hepatocellular carcinoma.

Acquired resistance remains a bottleneck for molecular-targeted therapy in advanced hepatocellular carcinoma (HCC). Metabolic adaptation and epigenetic remodeling are recognized as hallmarks of cancer that may contribute to acquired resistance. In various lenvatinib-resistant models, increased glycolysis leads to lactate accumulation and lysine lactylation of IGF2BP3. This lactylation is crucial for capturing PCK2 and NRF2 mRNAs, thereby enhancing their expression. This process reprograms serine metabolism and strengthens the antioxidant defense system. Additionally, altered serine metabolism increases the availability of methylated substrates, such as S-adenosylmethionine (SAM), for N6-methyladenosine (m6A) methylation of PCK2 and NRF2 mRNAs. The lactylated IGF2BP3-PCK2-SAM-m6A loop maintains elevated PCK2 and NRF2 levels, enhancing the antioxidant system and promoting lenvatinib resistance in HCC. Treatment with liposomes carrying siRNAs targeting IGF2BP3 or the glycolysis inhibitor 2-DG restored lenvatinib sensitivity in vivo. These findings highlight the connection between metabolic reprogramming and epigenetic regulation and suggest that targeting metabolic pathways may offer new strategies to overcome lenvatinib resistance in HCC.

Recently, changes in metabolites and metabolism-related enzymes related to tumor cell proliferation, metastasis, drug resistance, and immunosuppression have become a research hotspot, and researchers have attempted to determine the clinical correlation between specific molecular lesions and metabolic phenotypes. Convincing evidence shows that metabolic reprogramming is closely related to the proliferation, invasion, metastasis, and poor prognosis of malignant tumors. Therefore, targeting metabolic reprogramming is a new direction for cancer treatment. However, how molecular alterations in tumors contribute to metabolic diversity and unique targeting dependencies remains unclear. A full understanding of the underlying mechanisms of metabolic reprogramming in cancer may lead to better identification of therapeutic targets and the development of therapeutic strategies. Evidence for the importance of PCK1, a phosphoenolpyruvate carboxykinase 1, in tumorigenesis and development is accumulating. PCK1 can regulate cell proliferation and metastasis by remodeling cell metabolism. Additionally, PCK1 has "nonclassical" nonmetabolic functions, involving the regulation of gene expression, angiogenesis, epigenetic modification, and other processes, and has an impact on cell survival, apoptosis, and other biological activities, as well as the remodeling of the tumor immune microenvironment. Herein, we provide a comprehensive overview of the functions of PCK1 under physiological and pathological conditions and suggest that PCK1 is a potential target for cancer therapy. We also propose a future exploration direction for targeting PCK1 for cancer therapy from a clinical perspective. Finally, in view of the collective data, the results of our discussion suggest the potential clinical application of targeted PCK1 therapy in combination with chemotherapy and immunotherapy for cancer treatment.

Onions (Allium cepa L.) are nutritious vegetables; however, variations in processing methods can influence their chemical composition and functional properties. Raw processing and cooking are the two main food-processing methods for onions, but it is not clear what kind of changes these two methods cause. In the present study, ultrahigh-resolution liquid chromatography-mass spectrometry (UHPLC-MS) was utilized to observe the changes in onion composition during cooking and to investigate the protective effects of raw and cooked onion extracts against lead damage in vitro and at the cellular level. Many compounds were identified, including amino acids, nucleosides, flavonoids, and organosulfur compounds. Cooking causes changes in the content of numerous amino acids (e.g., DL-glutamine) in onions and increases nucleoside content (e.g., 5'-S-methyl-5'-thioadenosine, adenine). Both raw and cooked onion extracts can reduce neuronal cell damage caused by lead exposure, but cooking increased the free radical scavenging (e.g., DPPH, ABTS, hydroxyl radicals) and chelating of lead ions (up to about 25%) of the onion extracts. In conclusion, cooking can cause changes in the chemical composition of onions and increase their antioxidant and lead chelating capacity.

Blood glucose fluctuates severely in the diabetes (DM) and tumor microenvironment. Our previous works have found Hepatitis B virus X protein (HBx) differentially regulated metastasis and apoptosis of hepatoma cells depending on glucose concentration. We here aimed to explore whether HBx played dual roles in the angiogenesis of hepatocellular carcinoma varying on different glucose levels.

We collected conditioned medium from HBx-overexpressing cells cultured with two solubilities of glucose, and then applied to EA.hy926 cells. Alternatively, a co-culture cell system was established with hepatoma cells and EA.hy926 cells. We analyzed the angiogenesis of EA.hy926 cells with CCK8, wound-healing, transwell-migartion and tube formation experiment. ELISA was conducted to detect the secretion levels of angiogenesis-related factors. siRNAs were used to detect the P53-VEGF axis.

HBx expressed in hepatoma cells suppressed VEGF secretion, and subsequently inhibited the proliferation, migration and tube formation of EA.hy926 cells in a high glucose condition, while attenuating these in the lower glucose condition. Furthermore, the p53-VEGF axis was required for the dual role of HBx in angiogenesis. Additionally, HBx mainly regulated the nuclear p53.

These data suggest that the dual roles of HBx confer hepatoma cells to remain in a glucose-rich environment and escape from the glucose-low milieu through tumor vessels, promoting liver tumor progression overall. We exclusively revealed the dual role of HBx on the angiogenesis of liver tumors, which may shed new light on the mechanism and management strategy of HBV- and DM-related hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a malignant tumor characterized by a high mortality rate. The occurrence and progression of HCC are linked to oxidative stress. Glyoxalase-1 (GLO1) plays an important role in regulating oxidative stress, yet the underlying mechanism remains unclear. GLO1 may serve as a prognostic biomarker and therapeutic target for HCC.

Based on TCGA database hepatocellular carcinoma samples, we conducted a bioinformatics analysis to explore the correlation between GLO1 expression and HCC cell proliferation and viability. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis revealed that differentially expressed genes (DEGs) were mainly enriched in the cell cycle pathway. We analyzed the relationships between GLO1 and 24 genes enriched in the cell cycle pathway using a protein-protein interaction (PPI) network. Finally, experimental validation was performed to assess GLO1's impact on the distribution of cells at different cell cycle stages and on the proliferation and migration of HCC cells.

Our study demonstrated that GLO1 was overexpressed in HCC tissues and was associated with a poor prognosis. Data analysis indicated that overexpression of GLO1 activated the cell cycle pathway and positively correlated with expression of the majority of key cell cycle genes. Experimental validation showed that GLO1 expression affects the number of HCC cells in G2 and S phases and regulates HCC cell proliferation and migration.

GLO1 represents a promising therapeutic target for HCC, providing valuable insights into its role in the viability and proliferation of HCC cells.

The growing elderly population presents a significant concern, with the prolongation of life expectancy, aging diseases are becoming increasingly common. Resveratrol (RSV) has emerged as a promising compound for disease prevention. However, the effect of RSV on lifespan extension in different organisms, particularly the model organism silkworm, remains inconsistent. We conducted aging experiments using silkworm (B. mori) and employed transcriptomics to investigate the therapeutic effects of RSV on lifespan extension and healthy lifespan in silkworms. RSV increased the survival rate by 8.57 %-12.12 % and enhanced the antioxidant capacity of silkworms. Transcriptomic analysis demonstrated that genes in signaling pathways such as AMPK and FoxO were significantly upregulated. 16SrRNA sequencing of gut contents showed an increase in beneficial bacterial strains under the action of RSV. This study aims to enhance our understanding of lifespan regulation mechanisms using the silkworm model and provide new targets for anti-aging antioxidants research to delay the onset of age-related diseases.

Hepatocellular carcinoma (HCC) is a prevalent malignancy within the digestive system, known for its poor prognosis. Gluconeogenesis, a critical metabolic pathway, is responsible for the synthesis of glucose in the normal liver. This study aimed to examine the role of gluconeogenesis-related genes (GRGs) in HCC and evaluate their impact on the tumor microenvironment infiltration and drug sensitivity in HCC.

We retrieved gene expression and clinical pathological data of HCC from The Cancer Genome Atlas (TCGA) database. This dataset was utilized to develop a prognosis model. The data from The International Cancer Genome Consortium (ICGC) served as an independent validation cohort. A least absolute shrinkage and selection operator (LASSO) regression analysis was applied to a curated panel of GRGs to construct and validate the predictive model. Furthermore, unsupervised consensus clustering, based on the expression levels of GRGs, categorized HCC patients into distinct subgroups.

A four-gene prognostic model, referred to as GRGs, has been successfully developed with high accuracy and stability for the prediction of HCC patient prognosis. This model enables the stratification of patients into high or low risk groups based on individual risk scores, revealing significant differences in immune infiltration patterns and anti-tumor drug responses. Unsupervised consensus clustering analysis delineated four distinct subgroups of patients, each characterized by a unique prognosis and tumor immune microenvironment (TIME).

This study is the first to develop a prognostic model incorporating 4-GRGs that effectively predicts the prognosis, tumor microenvironment infiltration, and drug sensitivity in HCC patients. The model based on 4 GRGs may contribute to predict the prognosis, immunotherapy and chemotherapy response of HCC patients.

Mannose-binding lectin-associated serine protease 1 (MASP1) plays a crucial role in the complement lectin pathway and the mediation of immune responses. However, comprehensive research on MASP1 across various cancer types has not been performed to date. This study aimed to evaluate the significance of MASP1 in pan-cancer. The Cancer Genome Atlas (TCGA), UCSC Xena and Genotype Tissue Expression (GTEx) databases were used to evaluate the expression profiles, genomic features, prognostic relevance, and immune microenvironment associations of MASP1 across 33 cancer types. We observed significant dysregulation of MASP1 expression in multiple cancers, with strong associations between MASP1 expression levels and diagnostic value as well as patient prognosis. Mechanistic insights revealed significant correlations between MASP1 levels and various immunological and genomic factors, including tumor-infiltrating immune cells (TIICs), immune-related genes, mismatch repair (MMR), tumor mutation burden (TMB), and microsatellite instability (MSI), highlighting a critical regulatory function of MASP1 within the tumor immune microenvironment (TIME). In vitro and in vivo experiments demonstrated that MASP1 expression was markedly decreased in liver hepatocellular carcinoma (LIHC). Moreover, the overexpression of MASP1 in hepatocellular carcinoma (HCC) cell lines significantly inhibited their proliferation, invasion and migration. In conclusion, MASP1 exhibits differential expression in the pan-cancer analyses and might play an important role in TIME. MASP1 is a promising prognostic biomarker and a potential target for immunological research, particularly in LIHC.

The pathological proliferation and migration of vascular smooth muscle cells (VSMCs) are key processes during vascular neointimal hyperplasia (NIH) and restenosis. Phosphoenolpyruvate carboxy kinase 1 (PCK1) is closely related to a variety of malignant proliferative diseases. However, the role of PCK1 in VSMCs has rarely been investigated. This study aims to examine the role of PCK1 in the proliferation and migration of VSMCs and vascular NIH after injury. In vivo, extensive NIH and increased expression of PCK1 within the neointima are observed in injured arteries. Interestingly, the administration of adeno-associated virus-9 (AAV-9) carrying Pck1 short hairpin RNA (sh Pck1) significantly attenuates NIH and stenosis of the vascular lumen. In vitro, Pck1 small interfering RNA (si Pck1)-induced PCK1 silencing inhibits VSMC proliferation and migration. Additionally, silencing of PCK1 leads to reduced expression of dynamin-related protein 1 (DRP1) and attenuated mitochondrial fission. Lentivirus-mediated DRP1 overexpression markedly reverses the inhibitory effects of PCK1 silencing on VSMC proliferation, migration, and mitochondrial fission. Finally, PCK1 inhibition attenuates the phosphorylation of signal transducer and activator of transcription 3 (STAT3). Activation of STAT3 abolishes the suppressive effects of PCK1 silencing on DRP1 expression, mitochondrial fission, proliferation, and migration in VSMCs. In conclusion, PCK1 inhibition attenuates the mitochondrial fission, proliferation, and migration of VSMCs by inhibiting the STAT3/DRP1 axis, thereby suppressing vascular NIH and restenosis.

This study aimed to explore the involvement of phosphoenolpyruvate carboxykinase 2 (PCK2) in gefitinib-resistant non-small cell lung cancer (NSCLC) cells and assess its feasibility as a therapeutic target against gefitinib resistance.

Gefitinib-resistant cell lines, PC9GR and HCC827GR, were generated through progressive exposure of parental cells to escalating concentrations of gefitinib. Transcriptomic analysis encompassed the treatment of PC9 and PC9GR cells with gefitinib or vehicle, followed by RNA extraction, sequencing, and subsequent bioinformatic analysis. Cell viability was determined via CCK-8 assay, while clonogenic assays assessed colony formation. Apoptosis was detected utilizing the Annexin V-FITC/7AAD kit. Iron ion concentrations were quantified using FerroOrange. mRNA analysis was conducted through quantitative RT-PCR. Western blotting was employed for protein analysis. H&E and immunohistochemical staining were performed on tumor tissue sections.

The results revealed that depletion or inhibition of PCK2 significantly enhanced gefitinib's efficacy in inducing cell growth arrest, apoptosis, and ferroptosis in resistant NSCLC. Moreover, PCK2 knockdown led to the downregulation of key ferroptosis-related proteins, GPX4 and SLC7A11, while upregulating ASCL4. Conversely, overexpression of PCK2 in gefitinib-sensitive cells rendered resistance to gefitinib. In vivo experiments using a gefitinib-resistant xenograft model demonstrated that PCK2 silencing not only reduced tumor growth but also considerably increased the anti-tumor effect of gefitinib.

In conclusion, our study presents compelling evidence indicating that PCK2 plays a pivotal role in gefitinib resistance in NSCLC. The modulation of ferroptosis-related proteins and the involvement of Akt activation further elucidate the mechanisms underlying this resistance. Consequently, PCK2 emerges as a promising therapeutic target for overcoming gefitinib resistance in NSCLC, offering a new avenue for the development of more effective treatment strategies.

Reticulitermes flaviceps is an economically important pest in agriculture, forestry, and construction. Recent studies have shown an increase in research focusing on the anti-termite properties of plant essential oils, however, there remains a lack of information regarding the specific molecular mechanism involved. In this study, RNA-seq analysis was conducted on termites exposed to Mentha spicata essential oil (EO) and carvone, leading to the discovery of various genes that were expressed differentially under different treatment conditions. Numerous genes that exhibited a response to M. spicata EO and carvone found to be associated with stress-related pathways, such as drug metabolism cytochrome P450, glutathione metabolism, fatty acid metabolism, citric acid cycle, neuroactive ligand-receptor interaction, cell apoptosis, the AMPK signalling pathway, the mTOR signalling pathway, the longevity regulation pathway, ubiquitin-mediated protein hydrolysis, and the calcium signalling pathway. The up-regulation of genes (SPHK) associated with calcium channels, such as SPHK, indicates a potential mechanism of neurotoxicity, while the up-regulation of apoptosis-associated genes, including ACTB_G1, PYG, SQSTM1, RNF31, suggests a potential mechanism of cytotoxicity. The metabolism of M. spicata EO induces oxidative stress, elevates free Ca2+ levels in mitochondria, and initiates the generation of reactive oxygen species (ROS), ultimately resulting in programmed cell necrosis and apoptosis, as well as facilitating cellular autophagy. The monoterpenes exhibited neurotoxic and cytotoxic effects on R. flaviceps and could be exploited to advance termiticide development and eco-friendly termite control.

The maintenance of a highly functional metabolic epithelium in vitro is challenging. Metabolic impairments in primary human hepatocytes (PHHs) over time is primarily due to epithelial-to-mesenchymal transitioning (EMT). The immature hepatoma cell line HepG2 was used as an in vitro model to explore strategies for enhancing the hepatic phenotype. The phenotypic characterization includes measuring the urea cycle, lipid storage, tricarboxylic acid-related metabolites, reactive oxygen species, endoplasmic reticulum calcium efflux, mitochondrial membrane potentials, oxygen consumptions rate, and CYP450 biotransformation capacity. Expression studies were performed with transcriptomics, co-immunoprecipitation and proteomics. CRISPR/Cas9 was also employed to genetically engineer HepG2 cells. After confirming that PHHs develop an EMT phenotype, expression of tankyrase1/2 was found to increase over time. EMT was reverted when blocking tankyrases1/2-dependent poly-ADP-ribosylation (PARylation) activity, by biochemical and genetic perturbation. Wnt/β-catenin inhibitor XAV-939 blocks tankyrase1/2 and treatment elevated several oxygen-consuming reactions (electron-transport chain, OXHPOS, CYP450 mono-oxidase activity, phase I/II xenobiotic biotransformation, and prandial turnover), suggesting that cell metabolism was enhanced. Glutathione-dependent redox homeostasis was also significantly improved in the XAV-939 condition. Oxygen consumption rate and proteomics experiments in tankyrase1/2 double knockout HepG2 cells then uncovered PARylation as master regulator of aerobic-dependent cell respiration. Furthermore, novel tankyrase1/2-dependent PARylation targets, including mitochondrial DLST, and OGDH, were revealed. This work exposed a new mechanistic framework by linking PARylation to respiration and metabolism, thereby broadening the current understanding that underlies these vital processes. XAV-939 poses an immediate and straightforward strategy to improve aerobic activities, and metabolism, in (immature) cell cultures.

Phosphoenolpyruvate carboxykinase (PEPCK) plays a crucial role in gluconeogenesis, glycolysis, and the tricarboxylic acid cycle by converting oxaloacetate into phosphoenolpyruvate. Two distinct isoforms of PEPCK, specifically cytosolic PCK1 and mitochondrial PCK2, have been identified. Nevertheless, the comprehensive understanding of their dysregulation in pan-cancer and their potential mechanism contributing to signaling transduction pathways remains elusive.

We conducted comprehensive analyses of PEPCK gene expression across 33 diverse cancer types using data from The Cancer Genome Atlas (TCGA). Multiple public databases such as HPA, TIMER 2.0, GEPIA2, cBioPortal, UALCAN, CancerSEA, and String were used to investigate protein levels, prognostic significance, clinical associations, genetic mutations, immune cell infiltration, single-cell sequencing, and functional enrichment analysis in patients with pan-cancer. PEPCK expression was analyzed about different clinical and genetic factors of patients using data from TCGA, GEO, and CGGA databases. Furthermore, the role of PCK2 in Glioma was examined using both in vitro and in vivo experiments.

The analysis we conducted revealed that the expression of PEPCK is involved in both clinical outcomes and immune cell infiltration. Initially, we verified the high expression of PCK2 in GBM cells and its role in metabolic reprogramming and proliferation in GBM.

Our study showed a correlation between PEPCK (PCK1 and PCK2) expression with clinical prognosis, gene mutation, and immune infiltrates. These findings identified two possible predictive biomarkers across different cancer types, as well as a comprehensive analysis of PCK2 expression in various tumors, with a focus on GBM.

Protein succinylation modification is a common post-translational modification (PTM) that plays an important role in bacterial metabolic regulation. In this study, quantitative analysis was conducted on the succinylated proteome of wild-type and florfenicol-resistant Vibrio alginolyticus to investigate the mechanism of succinylation regulating antibiotic resistance. Bioinformatic analysis showed that the differentially succinylated proteins were mainly enriched in energy metabolism, and it was found that the succinylation level of phosphoenolpyruvate carboxyl kinase (PEPCK) was highly expressed in the florfenicol-resistant strain. Site-directed mutagenesis was used to mutate the lysine (K) at the succinylation site of PEPCK to glutamic acid (E) and arginine (R), respectively, to investigate the function of lysine succinylation of PEPCK in the florfenicol resistance of V. alginolyticus. The detection of site-directed mutagenesis strain viability under florfenicol revealed that the survival rate of the E mutant was significantly higher than that of the R mutant and wild type, indicating that succinylation modification of PEPCK protein may affect the resistance of V. alginolyticus to florfenicol. This study indicates the important role of PEPCK during V. alginolyticus antibiotic-resistance evolution and provides a theoretical basis for the prevention and control of vibriosis and the development of new antibiotics.

Liver cancer stem cells were found to rely on glycolysis as the preferred metabolic program. Phosphoenolpyruvate carboxylase 1 (PCK1), a gluconeogenic metabolic enzyme, is down-regulated in hepatocellular carcinoma and is closely related to poor prognosis. The oncogenesis and progression of tumors are closely related to cancer stem cells. It is not completely clear whether the PCK1 deficiency increases the stemness of hepatoma cells and promotes the oncogenesis of hepatocellular carcinoma. Herein, the results showed that PCK1 inhibited the self-renewal property of hepatoma cells, reduced the mRNA level of cancer stem cell markers, and inhibited tumorigenesis. Moreover, PCK1 increased the sensitivity of hepatocellular carcinoma cells to sorafenib. Furthermore, we found that PCK1 activated the Hippo pathway by enhancing the phosphorylation of YAP and inhibiting its nuclear translocation. Verteporfin reduced the stemness of hepatoma cells and promoted the pro-apoptotic effect of sorafenib. Thus, combined treatment with verteporfin and sorafenib may be a potential anti-tumor strategy in hepatocellular carcinoma.

Mitochondrial phosphoenolpyruvate carboxykinase (PCK2), a mitochondrial isoenzyme, supports the growth of cancer cells under glucose deficiency conditions in vitro. This study investigated the role and potential mechanism of PCK2 in the occurrence and development of Hepatocellular carcinoma (HCC). The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), and other databases distinguish the expression of PCK2 and verified by qRT-PCR and Western blotting. Kaplan-Meier was conducted to assess PCK2 survival in HCC. The potential biological function of PCK2 was verified by enrichment analysis and gene set enrichment analysis (GSEA). The correlation between PCK2 expression and immune invasion and checkpoint was found by utilizing Tumor Immune Estimation Resource (TIMER). Lastly, the effects of PCK2 on the proliferation and metastasis of hepatocellular carcinoma cells were evaluated by cell tests, and the expressions of Epithelial mesenchymal transformation (EMT) and apoptosis related proteins were detected. PCK2 is down-regulated in HCC, indicating a poor prognosis. PCK2 gene mutation accounted for 1.3% of HCC. Functional enrichment analysis indicated the potential of PCK2 as a metabolism-related therapeutic target. Subsequently, we identified several signaling pathways related to the biological function of PCK2. The involvement of PCK2 in immune regulation was verified and key immune checkpoints were predicted. Ultimately, after PCK2 knockdown, cell proliferation and migration were significantly increased, and N-cadherin and vimentin expression were increased. PCK2 has been implicated in immune regulation, proliferation, and metastasis of hepatocellular carcinoma, and is emerging as a novel predictive biomarker and metabolic-related clinical target.

Epigenetic and metabolic reprogramming alterations are two important features of tumors, and their reversible, spatial, and temporal regulation is a distinctive hallmark of carcinogenesis. Epigenetics, which focuses on gene regulatory mechanisms beyond the DNA sequence, is a new entry point for tumor therapy. Moreover, metabolic reprogramming drives hepatocellular carcinoma (HCC) initiation and progression, highlighting the significance of metabolism in this disease. Exploring the inter-regulatory relationship between tumor metabolic reprogramming and epigenetic modification has become one of the hot directions in current tumor metabolism research. As viral etiologies have given way to metabolic dysfunction-associated steatotic liver disease (MASLD)-induced HCC, it is urgent that complex molecular pathways linking them and hepatocarcinogenesis be explored. However, how aberrant crosstalk between epigenetic modifications and metabolic reprogramming affects MASLD-induced HCC lacks comprehensive understanding. A better understanding of their linkages is necessary and urgent to improve HCC treatment strategies. For this reason, this review examines the interwoven landscape of molecular carcinogenesis in the context of MASLD-induced HCC, focusing on mechanisms regulating aberrant epigenetic alterations and metabolic reprogramming in the development of MASLD-induced HCC and interactions between them while also updating the current advances in metabolism and epigenetic modification-based therapeutic drugs in HCC.