Background: N6-methyladenosine (m6A) methylation and ferroptosis assist long noncoding RNAs (lncRNAs) in promoting immune escape in hepatocellular carcinoma (HCC). However, the predictive value of m6A- and ferroptosis-related lncRNAs (mfrlncRNAs) in terms of immune efficacy remains unknown.Method: A total of 365 HCC patients with complete data from The Cancer Genome Atlas (TCGA) database were used as the training cohort, and half of them were randomly selected as the validation cohort. A total of 161 HCC patients from the International Cancer Genome Consortium (ICGC) database were used as external validation (ICGC cohort).Results: We first identified a group of specific lncRNAs associated with both m6A regulators and ferroptosis-related genes and then constructed prognosis-related mfrlncRNA pairs. Based on this, the mfrlncRNA signature was constructed using the least absolute shrinkage and selection operator (LASSO) analysis and Cox regression. Notably, the risk score of patients was proven to be an independent prognostic factor and was better than the TNM stage and tumor grade. Moreover, patients with high-risk scores had lower survival rates, higher infiltration of immunosuppressive cells (macrophages and Tregs), lower infiltration of cytotoxic immune cells (natural killer cells), poorer immune efficacy (both immunophenoscore and score of tumor immune dysfunction and exclusion), higher IC₅₀, and enrichment of the induced Treg pathway, which confirmed that the mfrlncRNA signature contributed to survival prediction and risk stratification of patients with HCC.Conclusions: The mfrlncRNA signature, which has great prognostic value, provides new clues for identifying “cold” and “hot” tumors and might have crucial implications for individualized therapy to improve the survival rate of patients with HCC.

Immunometabolism is an emerging field that explores the intricate interplay between immune cells and metabolism. Regulatory T cells (Tregs), which maintain immune homeostasis in immunometabolism, play crucial regulatory roles. The activation, differentiation, and function of Tregs are influenced by various metabolic pathways, such as the Mammalian targets of rapamycin (mTOR) pathway and glycolysis. Correspondingly, activated Tregs can reciprocally impact these metabolic pathways. Tregs also possess robust adaptive capabilities, thus enabling them to adapt to various microenvironments, including the tumor microenvironment (TME). The complex mechanisms of Tregs in metabolic diseases are intriguing, particularly in conditions like MASLD, where Tregs are significantly upregulated and contribute to fibrosis, while in diabetes, systemic lupus erythematosus (SLE), and rheumatoid arthritis (RA), they show downregulation and reduced anti-inflammatory capacity. These phenomena suggest that the differentiation and function of Tregs are influenced by the metabolic environment, and imbalances in either can lead to the development of metabolic diseases. Thus, moderate differentiation and inhibitory capacity of Tregs are critical for maintaining immune system balance. Given the unique immunoregulatory abilities of Tregs, the development of targeted therapeutic drugs may position them as novel targets in immunotherapy. This could contribute to restoring immune system balance, resolving metabolic dysregulation, and fostering innovation and progress in immunotherapy.

Ang-2 promotes lung cancer metastasis by increasing epithelial-mesenchymal transition Ang-2 promotes lung cancer metastasis by increasing epithelial-mesenchymal transition

High mobility group box 3 as an emerging biomarker in diagnosis and prognosis of hepatocellular carcinoma Wenjie Zheng,1,2,* Junling Yang,2,* Zhizhen Dong,3,* Li Wang,1 Miao Fang,1 Wei Wu,2 Dengfu Yao,1,2 Min Yao1 1Medical School of Nantong University, Nantong 226001, Jiangsu, China; 2Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu, China; 3Department of Diagnostics, Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu, China *These authors contributed equally to this work Purpose: High mobility group box 3 (HMGB3) is associated with hepatocytes malignant transformation by our previous work. We continued to investigate the diagnostic and prognostic values of HMGB3 for hepatocellular carcinoma (HCC). Patients and methods: Circulating HMGB3 levels were quantitatively detected in a cohort of 225 patients with chronic liver diseases by ELISA and compared with alpha-fetoprotein by the receiver operating characteristic curve. HMGB3 expression in tissues of 170 HCC was detected by tissue microarray and immunohistochemistry. Relationship between HMGB3 level and HCC prognosis was evaluated by the Kaplan–Meier curves and Cox regression model. Results: The incidence of serum HMGB3 >2.0 ng/mL was 75.6% in HCC (96/127), 20.8% in liver cirrhosis (10/48), 16.0% in chronic hepatitis (8/50), and none in healthy controls (0/49). Significant difference (P30.6% in their paracancerous tissues (52/170). HMGB3 expression was closely related to tumor size, TNM stage, poor survival, and high recurrence, suggesting an independent prognosis factor for HCC. Conclusion: HMGB3 with aberrant expression could be a novel diagnostic and prognostic marker for HCC. Keywords: hepatocellular carcinoma, HMGB3, diagnosis, prognosis, biomarker

Hepatocellular carcinoma (HCC) is an aggressive malignant tumor with poor prognosis. Using high-throughput sequencing, we identified a novel circRNA, circGNAO1, which is downregulated in HCC tissues compared to adjacent tissues. However, the potential functions and mechanisms of circGNAO1 in HCC metastasis remain unclear. qRT-PCR was used to detect the expression of circGNAO1, miR-182-5p, and FOXO1 in HCC cells and tissues. Bioinformatics analysis, RNA pull-down assyas, and dual-luciferase reporter assays were employed to verify the interaction between circGNAO1 and miR-182-5p. Functional experiments were conducted using circGNAO1 overexpression and knockdown cell lines, including Transwell, wound healing, and EdU assays. Liver metastasis models and subcutaneous xenograft mouse models were established to analyze the effect of circGNAO1 on HCC metastasis and growth in vivo. High-throughput sequencing and qRT-PCR results showed that the expression of circGNAO1 dramatically decreased in HCC tissues. Functionally, in vivo and in vitro experiments verified that overexpression of circGNAO1 inhibited the proliferation, migration, invasion and EMT of HCC cells, while knockdown of circGNAO1 promoted these behaviors. Mechanistically, we have demonstrated that circGNAO1 functions as a sponge for miR-182-5p to regulate FOXO1 expression, thereby activating the TGF-β/Smad3 signaling pathway and EMT process. circGNAO1 suppresses the progression and metastasis of HCC through the miR-182-5p/FOXO1 axis, and circGNAO1 may be an efficient therapeutic target in HCC.