Acute‐on‐chronic liver failure (ACLF) is a syndrome characterized by systemic inflammation with a high short-term mortality rate. Syndecan-1 (SDC-1) can independently predict the 90-day mortality of patients with septic shock. However, the role of SDC-1 in ACLF remains unknown. In this study, serum SDC-1 levels were examined in 2 cohorts, which included 174 ACLF patients. And a mouse ACLF model induced by tetrachloride, lipopolysaccharide, and D-galactosamine was established, to evaluate the effects of sulodexide and heparan sulfate (side chains of SDC-1) on ACLF in vivo. Baseline serum SDC-1 levels in 101 ACLF patients (847.72, 499.79–1511.37 ng/ml) were significantly higher than in healthy controls (33.58, 27.08–43.34 ng/ml) (P < 0.0001). The baseline SDC-1 levels of patients who died or accepted a liver transplantation within 90 days were markedly higher than those of patients who survived (P < 0.05). A novel prognostic model (UIAS) based on upper gastrointestinal bleeding, INR, age, and SDC-1 was developed. The AUROC of the UIAS score for 28-day deterioration in ACLF patients was 0.884, indicating an obviously greater predictive performance for the outcomes of ACLF than those of the Child‐Pugh (AUROC = 0.646), MELD (AUROC = 0.713), and COSSH‐ACLF II scores (AUROC = 0.713). Moreover, we found that heparan sulfate and sulodexide could increase the expression of SDC-1 and attenuate liver injury, by promoting liver regeneration and inhibiting cell apoptosis through the activation of JAK1/STAT3 signalling. Collectively, our findings suggest that SDC-1 represents a potential prognostic and therapeutic target for ACLF and should be further investigated.

We aim to comprehensively analyze and validate the prognostic efficacy of tetraspanin 4 (TSPAN4) and several other migrasome-related markers in hepatocellular carcinoma (HCC). The expression, diagnostic, and prognostic efficacy of five migrasome-related genes in HCC were analyzed using several databases. Five pairs of adjacent non-tumor tissues and HCC tissues were used to validate the expression. The prognostic efficacy of TSPAN4 was validated in a HCC cohort. TSPAN4 was knocked down in Huh-7 cells, EdU, and CCK-8, and wound healing assays were conducted to analyze its effects on cell proliferation and migration. In addition, transcriptomic sequencing was used to identify differentially expressed genes. Compared with those in normal tissues, four genes (TSPAN4, PIGK, NDST1, and CPQ) were elevated in liver hepatocellular carcinoma (LIHC), but not TSPAN7. Of these, only elevated TSPAN4 predicted unfavorable prognosis of HCC patients. The expression and prognostic efficacy of TSPAN4 were further confirmed in a HCC cohort (97 patients); and patients in the TSPAN4high group showed unfavorable overall survival (log-rank P = 0.0055). Functional analysis showed that TSPAN4 knockdown significantly suppressed cell migration, but not cell proliferation. Moreover, TSPAN4 knockdown induced disturbances of the metabolic pathways, mainly pentose and glucuronate interconversions. TPSAN4 is a promising prognostic and therapeutic target for HCC treatment and may be involved in the metabolic pathways that affect disease progression.

Epidemic and animal studies have reported that perfluoroalkyl and polyfluoroalkyl substances (PFASs) are strongly associated with liver injury; however, to date, the effects of PFASs on the hepatic microenvironment remain largely unknown. In this study, we established perfluorooctane sulfonic acid (PFOS)-induced liver injury models by providing male and female C57BL/6 mice with water containing PFOS at varying doses for 4 weeks. Hematoxylin and eosin staining revealed that PFOS induced liver injury in both sexes. Elevated levels of serum aminotransferases including those of alanine aminotransferase and aspartate transaminase were detected in the serum of mice treated with PFOS. Female mice exhibited more severe liver injury than male mice. We collected the livers from female mice and performed single-cell RNA sequencing. In total, 36,529 cells were included and grouped into 10 major cell types: B cells, granulocytes, T cells, NK cells, monocytes, dendritic cells, macrophages, endothelial cells, fibroblasts, and hepatocytes. Osteoclast differentiation was upregulated and the T cell receptor signaling pathway was significantly downregulated in PFOS-treated livers. Further analyses revealed that among immune cell clusters in PFOS-treated livers, Tcf7(+)CD4(+)T (+) T cells were predominantly downregulated, whereas conventional dendritic cells and macrophages were upregulated. Among the fibroblast subpopulations, hepatic stellate cells were significantly enriched in PFOS-treated female mice. CellphoneDB analysis suggested that fibroblasts interact closely with endothelial cells. The major ligand-receptor pairs between fibroblasts and endothelial cells in PFOS-treated livers were Dpp4_Cxcl12, Ackr3_Cxcl12, and Flt1_complex_Vegfa. These genes are associated with directing cell migration and angiogenesis. Our study provides a general framework for understanding the microenvironment in the livers of female mice exposed to PFOS at the single-cell level.

Radiotherapy is a common treatment for abdominal and pelvic tumors, while the radiation-induced intestinal injury (RIII) is one of the major side-effects of radiotherapy, which reduces the life quality and impedes the treatment completion of cancer patients. Previous studies have demonstrated that environmental pollutant microplastics led to various kinds of injury in the gut, but its effects on RIII are still uncovered. In this study, we fed the C57BL/6J mice with distilled water or 50 μg/d polystyrene microplastics (PSMPs) for 17 days and exposed the mice to total abdominal irradiation (TAI) at day 14. Then the severity of RIII was examined by performing histopathological analysis and microbial community analysis. The results demonstrated that PSMPs significantly aggravated RIII in small intestine rather than colon of mice upon TAI. PSMPs increased levels of the histopathological damage and the microbial community disturbance in mice small intestine, shown by the overabundance of Akkermansiaceae and the decrease of microflora including Lactobacillaceae, Muribaculaceae and Bifidobacteriaceae. In conclusion, our results suggested that more microplastics exposure might led to more severe RIII, which should be considered in patients’ daily diet adjustment and clinical radiotherapy plan evaluation. Furthermore, this study also called for the further researches to uncover the underlying mechanism and develop novel strategies to attenuate RIII in mice intestine.

Radiation can induce cellular three-dimensional (3D) genome reorganization. However, the exact functional relevance of spatial rearrangements to gene transcription remains unknown. First, we screened and profiled the global picture of the 3D genome structure reorganization in human hepatocellular carcinoma cells MHCC-LM3 that were irradiated with 4Gy X-ray at a concentration of 100 cGy/min for 4 min using the high-throughput chromosome conformation capture (Hi-C) technique. They were maped and analyzed at three levels: compartment, topologically associating domain (TAD) and TAD boundary, and loop. The regulatory relationships within gene transcription exerted by the related dynamic spatial structure were confirmed by ribonucleic acid sequencing (RNA-seq) and further experimentally confirmed by quantitative real-time polymerase chain reaction in the same treated cell samples. A significant increase in interchromosomal interactions was observed in the irradiated cells. The extent of the effect of dynamic compartment switches and disrupted and gained TAD boundaries on gene transcription was significantly greater than that of small differential chromatin loops. Genes in human leukocyte antigen (HLA) and C‑C motif chemokine ligand (CCL) gene clusters associated with TAD boundary alterations were considerably upregulated, and this effect was maintained 24 h post-radiation. We characterized the radiation-induced landscape map of the 3D genome in cells and elucidated the mechanism by which 3D genome reorganization spatially regulates gene transcription. This study provides a basis for further research directed toward understanding the role of structural alterations in gene expression.

BACKGROUND AND PURPOSE:Radiotherapy (RT) has a promising anti-tumor effect depending on its effects on both cancer cells and tumor immune microenvironment (TIME). As one of the most common alterations in hepatocellular carcinoma (HCC), wnt/β-catenin pathway activation, has been reported to induce radioresistance and suppressive TIME. In this study, we aim to explore the effect of wnt/β-catenin inhibitor ICG-001 on radiosensitivity and RT-related TIME of HCC and the underlying mechanism.MATERIALS AND METHODS:C57BL/6 and nude mouse tumor models were used to evaluate the efficacy of different treatments on tumor growth, recurrence and mice survival. Flow cytometry was performed to assess tumor infiltrating lymphocytes (TILs). DNA damage response (DDR) and radioresistance was investigated by colony formation assays, γ-H2AX and micronuclei measurements.RESULTS:The addition of ICG-001 to RT exhibited better anti-tumor and survival-prolong efficacy in C57BL/6 than nude mice. TILs analysis revealed that ICG-001 plus RT boosted the infiltration and IFN-γ production of TIL CD8+ T cells, meanwhile reduced the number of Tregs. Moreover, mechanistic study demonstrated that ICG-001 increased the radiation-induced DDR of HCC cells by suppressing p53, thus leading to stronger activation of cGAS/STING pathway. Utilization of cGAS/STING pathway inhibitors impaired the therapeutic effect of combination therapy. Furthermore, combination therapy led to stronger immunologic memory and tumor relapse prevention.CONCLUSIONS:Our findings showed that ICG-001 displayed both local and systematic effects by increasing radiosensitivity and improving immunity in HCC, which indicated that ICG-001 might be a potential synergetic treatment for radiotherapy and radioimmunotherapy in HCC patients.