Jinyu Zhu

BACKGROUND: In this study, we comprehensively analyzed genes related to ferroptosis and iron metabolism to construct diagnostic and prognostic models and explore the relationship with the immune microenvironment in HCC. METHODS: Integrated analysis, cox regression and the least absolute shrinkage and selection operator (LASSO) method of 104 ferroptosis- and iron metabolism-related genes and HCC-related RNA sequencing were performed to identify HCC-related ferroptosis and iron metabolism genes. RESULTS: Four genes (ABCB6, FLVCR1, SLC48A1 and SLC7A11) were identified to construct prognostic and diagnostic models. Poorer overall survival (OS) was exhibited in the high-risk group than that in the low-risk group in both the training cohort (P < 0.001, HR = 0.27) and test cohort (P < 0.001, HR = 0.27). The diagnostic models successfully distinguished HCC from normal samples and proliferative nodule samples. Compared with low-risk groups, high-risk groups had higher TMB; higher fractions of macrophages, follicular helper T cells, memory B cells, and neutrophils; and exhibited higher expression of CD83, B7H3, OX40 and CD134L. As an inducer of ferroptosis, erastin inhibited HCC cell proliferation and progression, and it was showed to affect Th17 cell differentiation and IL-17 signaling pathway through bioinformatics analysis, indicating it a potential agent of cancer immunotherapy. CONCLUSIONS: The prognostic and diagnostic models based on the four genes indicated superior diagnostic and predictive performance, indicating new possibilities for individualized treatment of HCC patients. Video Abstract.

Tumor-associated macrophages (TAMs) play an essential role in tumor progression, metastasis, and antitumor immunity. Ferroptosis has attracted extensive attention for its lethal effect on tumor cells, but the role of ferroptosis in TAMs and its impact on tumor progression have not been clearly defined. Using transgenic mouse models, this study determines that xCT-specific knockout in macrophages is sufficient to limit tumorigenicity and metastasis in the mouse HCC models, achieved by reducing TAM recruitment and infiltration, inhibiting M2-type polarization, and activating and enhancing ferroptosis activity within TAMs. The SOCS3-STAT6-PPAR-γ signaling may be a crucial pathway in macrophage phenotypic shifting, and activation of intracellular ferroptosis is associated with GPX4/RRM2 signaling regulation. Furthermore, that xCT-mediated macrophage ferroptosis significantly increases PD-L1 expression in macrophages and improves the antitumor efficacy of anti-PD-L1 therapy is unveiled. The constructed Man@pSiNPs-erastin specifically targets macrophage ferroptosis and protumoral polarization and combining this treatment with anti-PD-L1 exerts substantial antitumor efficacy. xCT expression in tumor tissues, especially in CD68+ macrophages, can serve as a reliable factor to predict the prognosis of HCC patients. These findings provide further insight into targeting ferroptosis activation in TAMs and regulating TAM infiltration and functional expression to achieve precise tumor prevention and improve therapeutic efficacy.

A 63-day feeding trial was conducted in northern snakehead to observe the effects of a dietary soybean meal substitution on the microbiota community, morphology and inflammatory cytokine gene expression in the intestine. Four isonitrogenous and isoenergetic diets containing increasing levels of soybean meal were used to replace 0%, 25%, 50% and 75% of the defatted fishmeal (diets are referred to G1, G2, G3 and G4, respectively). Different dietary soybean meal substitutions significantly affected the intestinal microbiota composition. At the phylum level, Firmicutes abundance was the lowest in the G4 group, in contrast with Proteobacteria, Bacteroidetes and Planctomycetes. At the genus level, significantly lower abundance of Lactococcus, Geobacillus, Pseudomonas, Streptococcus, Bacillus and Acinetobacter,but higher abundance of Cetobacterium, Planctomyces, Shewanella, Thermomonas, Rubrivivax and Carnobacterium was observed in fish fed the G4 diet. With increased dietary soybean meal, the thickness of the muscularis, the height of the fold and the height of the microvillus in the distal intestine decreased, but the relative expression of IL-1β, IL-10 and IL-17F was significantly up-regulated. In conclusion, more emphasis should be placed on the functionality of intestinal microbiota and the pathogenesis of mucosal inflammation to assess the effects of diet and fish intestinal health through intestinal microbiota profiling.

Introduction: The development and prognosis of HCC involve complex molecular mechanisms, which affect the effectiveness of its treatment strategies. Tumor mutational burden (TMB) is related to the efficacy of immunotherapy, but the prognostic role of TMB-related genes in HCC has not yet been determined clearly. Objectives: In this study, we identified TMB-specific genes with good prognostic value to build diagnostic and prognostic models and provide guidance for the treatment of HCC patients. Methods: Weighted gene co-expression network analysis (WGCNA) was applied to identify the TMB-specific genes. And LASSO method and Cox regression were used in establishing the prognostic model. Results: The prognostic model based on SMG5 and MRPL9 showed patients with higher prognostic risk had a remarkedly poorer survival probability than their counterparts with lower prognostic risk in both a TCGA cohort (P < 0.001, HR = 1.93) and an ICGC cohort (P < 0.001, HR = 3.58). In addition, higher infiltrating fractions of memory B cells, M0 macrophages, neutrophils, activated memory CD4 + T cells, follicular helper T cells and regulatory T cells and higher expression of B7H3, CTLA4, PD1, and TIM3 were present in the high-risk group than in the low-risk group (P < 0.05). Patients with high prognostic risk had higher resistance to some chemotherapy and targeted drugs, such as methotrexate, vinblastine and erlotinib, than those with low prognostic risk (P < 0.05). And a diagnostic model considering two genes was able to accurately distinguish patients with HCC from normal samples and those with dysplastic nodules. In addition, knockdown of SMG5 and MRPL9 was determined to significantly inhibit cell proliferation and migration in HCC. Conclusion: Our study helps to select patients suitable for chemotherapy, targeted drugs and immunotherapy and provide new ideas for developing treatment strategies to improve disease outcomes in HCC patients.

INTRODUCTION: Inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn's disease (CD), is a group of chronic recurrent and incurable gastrointestinal diseases with an unknown etiology that leads to a high risk of developing colitis-associated colorectal cancer (CRC). OBJECTIVES: In this study, we measured the expression characteristics of MELK in IBD and CRC tissues and explored the regulatory effect of OTSSP167 (a MELK-selective inhibitor) on the mice models of colitis and colitis-associated carcinogenesis and analyzed the specific molecular mechanisms. METHODS: DSS-induced colitis and colitis-associated carcinogenesis (CAC) model were treated with MELK inhibitor OTSSP167 then the fight against effect of OTSSP167 in the clinical symptoms of colitis and CAC was measured. In addition, underlying mechanism of OTSSP167 treatment in vitro and vivo including anti-ferroptosis and anti-inflammatory response effect was further explored. RESULTS: We found that pharmacological inhibition of MELK was indicated to significantly alleviate the inflammatory response in mice with colitis, reduce intestinal damage, and effectively inhibit the occurrence and progression of colitis-propelled carcinogenesis, which was closely related to the regulation of gut microbial composition, and OTSSP167-mediated fecal microbiota transplantation effectively alleviated DSS-induced colitis. In addition, OTSSP167 treatment obviously inhibited ferroptosis in the intestinal tissue and suppressed macrophage infiltration and M1 polarization, which reduced the secretion of pro-inflammatory factors. Further exploration of the molecular mechanism revealed that OTSSP167 inhibited AKT/IKK/P65 and ERK/IKK/P65 signaling cascades both in vivo and in vitro, which may help alleviate intestinal inflammation and control the occurrence of cancer. CONCLUSION: Our findings lay a theoretical foundation for the use of OTSSP167 as a treatment for IBD and its inhibition of the occurrence of colitis-associated carcinogenesis; additionally, MELK may be a potentially effective target molecule, thus providing more options for clinical treatment.