Jiatao Liu

Shuojiao Li, Peng Rao, Wenxian Yu, Yue Tang, Xuanpeng Jiang and Jiatao Liu. Biomolecules & Therapeutics -0001;0:. https://doi.org/10.4062/biomolther.2025.037

Aim: The reprogramming of lipid metabolism can markedly enhance the nutritional adaptability of tumor cells to the glucose-deficient and hypoxic tumor microenvironment, which holds profound significance for the development and metastasis of liver cancer. Nevertheless, the alterations of lipid metabolism under stress conditions and the specific mechanisms remain ambiguous. The current study aimed to explore the molecular interaction between endoplasmic reticulum (ER) stress and lipid metabolism in hepatocellular carcinoma (HCC) using bioinformatics analysis, and further verify the role of core hub genes and offer potential targets for diagnosing and treating HCC. Methods: Differentially expressed lipid-related genes (DLRGs) were identified via cross-crossing differentially expressed genes (DEGs) in the TCGA-LIHC program and lipid metabolism-related genes in the Genecards database. Identification of hub genes was achieved by constructing a protein-protein interaction (PPI) network, gene ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG). Disease correlation analysis was performed in the Comparison of Toxicology Database, receiver operating characteristic (ROC) curve and Kaplan-Meier curve analyses were performed for the hub genes, and the CIBERSORT algorithm was employed to assess immune infiltration. The role of acetyl-CoA carboxylase 1 (ACACA) in HCC was evaluated by Western blotting, polymerase chain reaction, immunohistochemistry, and CCK-8 assay. Results: In total, 131 DLRGs were identified, comprising 70 upregulated and 61 downregulated. PPI analysis identified 20 hub DLRGs, while ROC curve analysis and Kaplan-Meier analysis further revealed that ACACA, LCAT, APOC3, LPA and PON1 may hold diagnostic and prognostic value for HCC patients. More importantly, ACACA overexpression was related to unfavorable overall survival (OS) and adverse pathological characteristics in HCC patients. In addition, both free fatty acid (FFA) and tunicamycin (TM) could activate ER stress and enhance the expression of ACACA in HCC. Interestingly, inhibition of ER stress or fatty acid synthesis using 4-phenylbutyric acid (4-PBA) or fenofibrate significantly reduced the expression of ACACA, and fenofibrate inhibits HCC cell proliferation. Conclusion: The study identifies a novel core lipid metabolism-related gene called ACACA, which has prognostic and therapeutic potential for HCC. We also provide a deep understanding of lipid metabolism correlated with ER stress in the progression of HCC, offering new opportunities for the identification of biological targets and the development of drugs and treatments for HCC patients.

Objective: The aim of this study was to establish a simple and sensitive high-performance liquid chromatography method for therapeutic drug monitoring of venetoclax (VEN) and optimize regimens. Methods: The analysis required the extraction of a 50 μl plasma sample and the precipitation of proteins using acetonitrile extraction. The chromatographic method employed a mobile phase of acetonitrile: 0.5% KH₂PO₄ (pH 3.5) (60/40, v/v) on a Diamond C₁₈ (4.6 mm × 250 mm, 5 μm) column at a flow rate of 1.0 ml/min. The quantitative method was validated based on standards described in ‘Bioanalytical Method Validation: Guidance for Industry’ published by the US Food and Drug Administration (FDA). Results: The calibration curve was linear (R ² = 0.9998) over the range of 75–4800 ng/ml, with limits of quantification of 25 ng/ml. The coefficients of intraday and interday validation, specificity, recovery, and stability all met the criteria of FDA guidance. The method was successfully applied to analyze VEN concentrations in 30 cases of acute myeloid leukemia patients. The peak concentration (C _max) was 1881.19 ± 756.61 ng/ml, while the trough concentration (C _min) was 1212.69 ± 767.92 ng/ml in acute myeloid leukemia patients. Conclusion: Our study establishes a simple, precise, and sensitive high-performance liquid chromatography method for monitoring VEN and confirms its applicability for therapeutic drug monitoring of VEN in hematological cancers.

Introduction: The gut microbiota plays an important role in the development of non-alcoholic steatohepatitis (NASH), but the underlying mechanism is unclear. It has been found that the transcription factor XBP1s plays an important role in regulating inflammation and lipid metabolism and maintaining the integrity of intestinal barrier. However, whether XBP1s modulates the development of NASH by regulating the integrity of the intestinal barrier and altering the composition of the gut microbiota remains unknown.Methods: Mice fed with a fat-, fructose-, cholesterol-rich (FFC) diet for 24 weeks successfully established the NASH model, as demonstrated by significant hepatic steatosis, inflammation, hepatocyte injury and fibrosis. The profile of gut microbiota dynamically changed with the different stages of NAFLD via 16S rDNA sequencing the feces from mice fed with FFC diet for 0, 12, or 24 weeks or NASH mice treated with siRNA-loaded folic acid-modified TPGS (hereafter named FT@XBP1).Results: NASH mice had significantly higher abundance of Firmicutes, Blautia and Bacteroides, and lower abundance of Bifidobacterium and GCA-900066575. FT@XBP1 supplementation had a significantly attenuated effect on FFC diet-induced weight gain, hepatic fat accumulation, dyslipidemia, inflammatory cytokines, ER stress and fibrosis. In particularly, FT@XBP1 modulates the composition of the intestinal flora; for example, NASH mice demonstrated higher abundance of Blautia and Bacteroides, and lower abundance of Actinobacteriota, Muribaculaceae and Bifidobacterium, which were partially restored by FT@XBP1 treatment. Mechanistically, FT@XBP1 increased the expression of ZO-1 in the intestine and had the potential to restore intestinal barrier integrity and improve antimicrobial defense to alleviate enterogenic endotoxemia and activation of inflammatory signaling pathways.Discussion: Regulation of the key transcription factor XBP1s can partially restore the intestinal microbiota structure, maintain the integrity of intestinal mucosal barrier, and prevent the progression of NASH, providing new evidence for treating NASH.

Macrophages show high plasticity and play a vital role in the progression of metabolic dysfunction-associated steatohepatitis (MASH). X-box binding protein 1 (XBP1), a key sensor of the unfolded protein response, can modulate macrophage-mediated pro-inflammatory responses in the pathogenesis of MASH. However, how XBP1 influences macrophage plasticity and promotes MASH progression remains unclear. Herein, we formulated an Xbp1 siRNA delivery system based on folic acid modified D-α-tocopheryl polyethylene glycol 1000 succinate nanoparticles (FT@XBP1) to explore the precise role of macrophage-specific Xbp1 deficiency in the progression of MASH. FT@XBP1 was specifically internalized into hepatic macrophages and subsequently inhibited the expression of spliced XBP1 both in vitro and in vivo. It promoted M1-phenotype macrophage repolarization to M2 macrophages, reduced the release of pro-inflammatory factors, and alleviated hepatic steatosis, liver injury, and fibrosis in mice with fat-, fructose- and cholesterol-rich diet-induced MASH. Mechanistically, FT@XBP1 promoted macrophage polarization toward the M2 phenotype and enhanced the release of exosomes that could inhibit the activation of hepatic stellate cells. A promising macrophage-targeted siRNA delivery system was revealed to pave a promising strategy in the treatment of MASH.