Shihai Liu

Traditional pharmacokinetic evaluation of polysaccharide-based drugs often assumes that tissue accumulation reflects physical deposition of the administered polymer. However, large, highly charged sulfated polysaccharides have limited passive intestinal permeability, and the mechanisms by which orally administered polymers affect distal organs remain unclear. Here, we mapped spatiotemporal monosaccharide distributions across five vital organs after oral administration of two low-molecular-weight fucoidan fractions, LF1 and LF2, in ICR mice. Strict time-matched controls revealed marked circadian baseline fluctuations in serum monosaccharides, emphasizing the need for continuous baseline correction in glycan pharmacokinetic studies. Although fucose and galactose were the dominant constituents of the administered LMWFs, neither increased in serum at any sampled time point, arguing against bulk systemic absorption. In contrast, LF2 induced a significant serum elevation of N-acetylglucosamine at 14 h, despite this monosaccharide being absent from both fractions, providing systemic evidence of endogenous glycan remodeling. Spatially normalized multivariate analysis further identified lung-enriched accumulation of galactose, mannose, and N-acetylglucosamine. Mass-balance modeling showed that accumulated tissue monosaccharide mass exceeded the total administered dose, inconsistent with simple mass addition. These findings suggest that oral LMWFs act as biological effectors, either at analytically undetectable concentrations or through gut–lung signaling, to promote in situ pulmonary glycan anabolism.

Objectives: Liver cancer is one of the most fatal malignancies globally, with hepatocellular carcinoma (HCC) accounting for the majority of cases. A hallmark of HCC is its metabolic reprogramming, characterized by aerobic glycolysis (the Warburg effect), which fuels aggressive tumor growth and progression. Recent evidence highlights the role of transcription factors, such as upstream stimulatory factor 1 (USF1), in the metabolic reprogramming of cancer. However, the specific mechanisms by which USF1 regulates metabolism in liver cancer remain to be fully elucidated. Understanding these mechanisms is critical for identifying novel therapeutic targets for the management of HCC. Methods: This study utilized hepatocellular carcinoma cell lines (Hep3B and Huh7) and a murine xenograft model to investigate the regulatory role of USF1 in liver cancer metabolism. Functional assays included RNA interference, dual-luciferase reporter assays, ChIP-qPCR, and extracellular flux analysis. Furthermore, data from 374 liver cancer patients were retrospectively analyzed to assess the prognostic significance of USF1. Results: Our results demonstrate that USF1 promotes glycolysis in liver cancer by transcriptionally upregulating pyruvate dehydrogenase kinase 1 (PDK1). Knockdown of USF1 reduced glycolysis, lactate production, and ATP levels, while decreasing PDK1 expression. ChIP-qPCR confirmed that USF1 binds to the PDK1 promoter, driving PDK1 expression at the transcriptional level. Moreover, USF1 modulates glycolysis through the Wnt/β-catenin signaling pathway. In vivo experiments showed that silencing USF1 suppresses tumor growth, an effect partially reversed by PDK1 overexpression. Conclusions: This study provides the first comprehensive evidence of the USF1–PDK1 axis as a critical regulator of glycolysis and proliferation in hepatocellular carcinoma. Our findings highlight the therapeutic potential of targeting the USF1-PDK1 signaling pathway for the treatment of liver cancer.

Gastric cancer (GC) is one of the most common malignancies globally, with notable morbidity and mortality rates. Despite advances in surgical techniques and adjuvant therapies, recurrence and metastasis remain major challenges, highlighting the need for novel biomarkers and therapeutic targets. Long non‑coding RNAs (lncRNAs) have emerged as key regulators in various types of cancer, including GC, which can influence tumor progression through diverse mechanisms. LINC00467, in particular, has been implicated in non‑small cell lung cancer, hepatocellular carcinoma and colorectal cancer, but the role of LINC00467 in GC remains poorly understood. The present study aimed to elucidate the role of LINC00467 in GC progression by investigating its expression patterns, functional impact on cellular behaviors and underlying molecular mechanisms. The expression levels of LINC00467 were evaluated in the GEPIA database of human gastric cancer samples, which demonstrated LINC00467 upregulation in 60 tumor tissue samples from patients with GC compared with that of paired para‑cancerous control tissues. Functionally, LINC00467 promoted glycolysis in GC cells and enhanced their proliferative, migratory and invasive activities. From a mechanistic perspective, LINC00467 was able to bind to microRNA (miR)‑141‑3p in GC cells and a negative correlation between miR‑141‑3p and LINC00467 expression was observed in GC tissue samples. Inhibition of miR‑141‑3p partially reversed the effects of LINC00467 knockdown on GC cell malignancy and LINC00467 was further found to control the expression of the miR‑141‑3p target gene dihydropyriminidase‑like 3 (DPYSL3) in GC cells. Furthermore, lactate accumulation from glycolysis activated the AKT signaling pathway to promote the transcriptional expression of LINC00467 in GC cells and led to persistent glycolysis and GC cell invasion. The present study findings suggested that LINC00467 potentially controls GC progression via regulation of the miR‑141‑3p/DPYSL3 pathway.

Background and Objective: Lactic acid is a metabolite of glycolysis produced in the body, and its production is thought to be a mechanism by which cancer cells evade immune surveillance. Immune evasion and metabolic changes are well established as basic hallmarks of cancer. Although lactate has long been considered a waste product, it is now generally recognized to be a versatile small-molecule chemical that plays an important part in the tumor microenvironment (TME), with increased lactate production linked to the development of human malignancies. Metabolism in liver cancer is redirected toward glycolysis, which enhances the production of metabolic compounds used by tumor cells to produce proteins, lipids, and nucleotides, enabling them to maintain high proliferation rates and to establish the TME. Dysregulation of metabolic activity in liver cancer may impair antitumor responses owing to the immunosuppressive activity of the lactate produced by anaerobic glycolytic rates in tumor cells. This review primarily explores the link connection between lactic acid and the TME; evaluates the role of lactic acid in the occurrence, metastasis, prognosis, and treatment of liver cancer. Additionally, it investigates the associated pathways as potential targets for liver cancer treatment. Methods: Literature searches were conducted in PubMed, Web of Science, and Google Scholar, with the publication date of the most recent article included being January 2024. After eliminating duplicate articles and less relevant articles through titles and abstracts, we selected 113 articles for this review. We categorized references into two categories. One is to classify the content into lactate-related, liver cancer-related and tumor metabolism-related. The other is to classify the article types, which are divided into reviews, research articles and clinical trials. Additionally, we consulted the reference lists of the relevant articles to ensure coverage was comprehensive and unbiased. Key Content and Findings: The connection between lactic acid and the TME has recently become an area of intense research interest, and many related articles have been published in this field. The main finding of this review is to summarize the proven link between lactate and the TME and its possible impact on the TME of liver cancer. And analyzed the potential of lactate in liver cancer treatment and prognosis prediction. Conclusions: Lactate may be key to developing novel approaches in the future treatment of liver cancer. Related research on the combination of classic therapies and molecular targeted drugs may provide innovative medicines that more selectively regulate immune cell activity.

Hepatocellular carcinoma (HCC) is a highly prevalent primary liver carcinoma and the main cause of deaths (linked with cancer) across the globe. Despite advancements in prevention strategies, testing, and technological advances in diagnosis and treatment, the occurrence and fatality rate of HCC continue to rise. In recent decades, the approval of immune checkpoint inhibitors (ICIs) has transformed palliative treatment for liver cancer. However, the majority of patients with liver cancer do not respond to these treatments. Herein, we elaborated the microenvironment of the liver cancer and candidate immunotherapies based on activating the antitumor activity of myeloid, NK and T cells, chimeric antigen receptors-T or -NK cells, vaccines, oncolytic viruses, and combination therapies, as well as the challenges and opportunities of immunotherapies in liver cancer. This review also explores the rationale, molecular foundation, and supporting preclinical evidence for immunotherapies in HCC, available clinical evidence, and current immunotherapeutic clinical studies.

Background: Long noncoding RNAs (lncRNAs) are involved in a diverse array of biological processes. While lncRNAs are commonly upregulated in hepatocellular carcinoma (HCC), the specific regulatory roles they play in this oncogenic context require further study and clarification. Although HULC (lncRNA highly upregulated in liver cancer) is involved in disease pathogenesis, its precise role in this context remains unclear.Methods: Here, we have explored the mechanistic relevance of HULC expression by assessing its expression in patient samples. The importance of this lncRNA in the onset and progression of HCC was investigated through in vitro approaches including Western blotting, quantitative PCR, Transwell assays, electron microscopy, wound healing assays, and real‐time cell analysis (RTCA). Additionally, the in vivo functions of this lncRNA were assessed using an orthotopic HCC xenograft in nude mouse model system.Results: HULC was identified as a lncRNA that is highly upregulated in human liver tumors. In vitro, HULC was able to promote HCC malignancy, although its excess overexpression also led robust autophagic induction, promoting the increased expression of autophagy‐associated genes including LC3 and Beclin‐1. At a mechanistic level, HULC was able to promote the phosphorylation of p65 and IkBkB thus enhancing autophagy by increasing LC3II levels in a manner dependent upon the NF‐κB pathway. HULC downregulation was also linked to impaired orthotopic HCC tumor growth in vivo. The link between HULC and autophagy may play a role in disease progression.Conclusions: These results suggest that HULC is an oncogenic lncRNA, and may thus offer value as a prognostic biomarker and promoter of HCC development, in addition to being a potential therapeutic target in this cancer type.

Deoxythymidilate kinase (DTYMK) has been identified as a putative oncogene associated with the incidence of hepatocellular carcinoma (HCC), but the mechanisms whereby it regulates this cancer type remain uncertain. The present study was therefore designed to explore the role of DTYMK in HCC and to evaluate the underlying molecular mechanisms. MiRNAs associated with DTYMK expression levels in HCC were identified through analyses of both clinical samples and publically available gene expression datasets. We then assessed the putative functions of DTYMK and miR-148b-3p in this oncogenic context through studies of HCC cells and a murine xenograft model system. Correlation analyses and in vitro experiments led us to confirm DTYMK as a target of miR-148b-3p. In addition, we assessed dTTP levels associated with the DTYMK pathway in HCC cells to understand the functional implications of our experimental findings. We found that HCC tissues and cells exhibited marked DTYMK upregulation and miR-148b-3p downregulation, with the expression levels of DTYMK and miR-148b-3p being negatively correlated with one another. The impact of overexpressing DTYMK in tumor cells was partially reversed upon cellular transfection with miR-148b-3p mimics, providing conclusive evidence that DTMYK is a target of this miRNA. Importantly, DTYMK-related dTTP levels were also impacted by miR-148b-3p mimic transfection. DTYMK is a key regulator of HCC progression, and its expression is suppressed by miR-148b-3p, suggesting that this miR-148b-3p/DTYMK regulatory axis may be amenable to therapeutic targeting in patients with HCC.

Hepatocellular carcinoma (HCC) is a prevalent and highly aggressive cancer. Long non‐coding RNAs (lncRNAs) are recognized as potential molecular targets for HCC and are currently under increased research focus. Here, we investigate the regulatory processes underlying the axis of the lncRNA taurine upregulated gene 1 (TUG1), Upstream Transcription Factor 1 (USF1), and reactive oxygen species modulator 1 (ROMO1) in the propagation and metastasis of HCC cells. Distribution of lncRNA TUG1 was found to be prominent in HCC cell cytoplasm and nuclei. LncRNA TUG1 conscripted the USF1 transcription factor to enhance the promoter function of ROMO1. Enlisting the USF1 transcription factor to increase ROMO1 expression following upregulation of TUG1 lncRNA enhanced HCC Huh7 cell proliferation, motility, and metastasis. Rapid tumor proliferation in nude mice provided in vivo verification. The importance of the lncRNA TUG1/USF1/ROMO1 complex as a target for HCC therapy is a key result of this investigation which is exemplified by its role in regulating the proliferation, motility, and metastasis of HCC cells.