Research insights into the chemokine-like factor (CKLF)-like MARVEL transmembrane domain-containing family (CMTM): their roles in various tumors.

The chemokine-like factor (CKLF)-like MARVEL transmembrane domain-containing (CMTM) family includes CMTM1-8 and CKLF, and they play key roles in the hematopoietic, immune, cardiovascular, and male reproductive systems, participating in the physiological functions, cancer, and other diseases associated with these systems. CMTM family members activate and chemoattract immune cells to affect the proliferation and invasion of tumor cells through a similar mechanism, the structural characteristics typical of chemokines and transmembrane 4 superfamily (TM4SF). In this review, we discuss each CMTM family member's chromosomal location, involved signaling pathways, expression patterns, and potential roles, and mechanisms of action in pancreatic, breast, gastric and liver cancers. Furthermore, we discuss several clinically applied tumor therapies targeted at the CMTM family, indicating that CMTM family members could be novel immune checkpoints and potential targets effective in tumor treatment.

Abnormal low expression of SFTPC promotes the proliferation of lung adenocarcinoma by enhancing PI3K/AKT/mTOR signaling transduction.

The abnormality of surfactant protein C (SFTPC) has been linked to the development of a number of interstitial lung diseases, according to mounting evidence. Nonetheless, the function and mechanism of SFTPC in the biological progression of lung adenocarcinoma (LUAD) remain unclear. Analysis of public datasets and testing of clinical samples suggested that SFTPC expression was abnormally low in LUAD, which was associated with the onset and poor prognosis of LUAD. The SFTPC-related risk score was derived using least absolute shrinkage and selection operator Cox regression as well as multivariate Cox regression. The risk score was highly correlated with tumor purity and tumor mutation burden, and it could serve as an independent prognostic indicator for LUAD. Low-risk LUAD patients may benefit more from CTLA-4 or/and PD-1 inhibitors. Overall, the risk score is useful for LUAD patient prognostication and treatment guidance. Moreover, in vitro and in vivo experiments demonstrated that SFTPC inhibits the proliferation of LUAD by inhibiting PI3K/AKT/mTOR signaling transduction. These results reveal the molecular mechanism by which SFTPC inhibits the proliferation of LUAD and suggest that SFTPC could be a new therapeutic target for LUAD.

Small-molecule nanoprodrug with high drug loading and EGFR, PI3K/AKT dual-inhibiting properties for bladder cancer treatment.

Bladder cancer (BCa) is one of the most common malignancies worldwide. Although multiple efforts have been made, the 5-year survival rate of patients with BCa remains unchanged in recent years. Overexpression of the epidermal growth factor receptor (EGFR) is found in ≈74% of BCa tissue specimens; however, current EGFR-based targeted therapies show little benefit for BCa patients, as the EGFR downstream pathways appear to be circumvented by other receptor tyrosine kinases (RTKs). In this study, two natural products are identified, namely triptolide (TPL) and hesperidin (HSP), that target and inhibit the EGFR and its downstream PI3K/AKT pathway in BCa. To synergistically combine triptolide and hesperidin, a succinic acid linker was employed to conjugate them and formed an amphiphilic TPL-HSP EGFR-targeting prodrug (THE), which further self-assembled to generate nanoparticles (THE NPs). These NPs allowed the EGFR-targeted delivery of the triptolide and hesperidin, and simultaneous inhibition of the EGFR and PI3K/AKT both in vitro and in vivo. This study provides a promising EGFR-targeted delivery approach with the dual inhibition of the EGFR and PI3K/AKT, while also exhibiting a high drug loading and low toxicity. Our formulation may be a suitable option to deliver natural products for BCa treatment by EGFR-targeted therapy.

SPP2 plays a role in the tumorigenesis of hepatocellular carcinoma: A bioinformatic based analysis. / 基于生物信息学分析SPP2在肝癌发生过程中的作用（英文）.

OBJECTIVES: Hepatocellular carcinoma (HCC) patients at the same stage exhibit different prognosis, and the underlying molecular mechanism remains unclear. This study aims to identify the key genes impacting the prognosis of HCC patients. METHODS: Differentially expressed gene analyses were performed between HCC samples and normal ones, and between patients with long overall survival (OS) and those with short OS, in TCGA-LIHC and GSE14520 datasets. The Kaplan-Meier method with log-rank test was used to evaluate the role of secreted phosphoprotein 2 (SPP2) in the prognosis of HCC patients. Gene set enrichment analysis (GSEA) was used to understand the difference of enriched signaling pathways between SPP2-stratified HCC subgroups. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed to predict the potential functional pathways in which SPP2 might participate. RESULTS: SPP2 was significantly down-regulated in tumors when compared with normal tissues, or in tumor samples with short OS when compared with those with long OS [fold change (FC)>2 and false discovery rate (FDR)<0.05]. Low expression of SPP2 was associated with worse clinicopathological features like vascular invasion (P=1.6e-05), poor cancer status (with tumor, P=0.021), advanced T stage (T3 or T4, P=4.5e-04), advanced TNM stage (stage III or IV, P=3.1e-04), and with unfavorable prognosis (shorter OS, P=0.002). Gene enrichment analyses revealed that SPP2 might involve in the metabolic homeostasis of HCC and in the development of liver fibrosis and cirrhosis. CONCLUSIONS: SPP2 might inhibit the development of liver fibrosis and cirrhosis and the tumorigenesis of HCC, and analogs of SPP2 might be potential drugs in the prevention of these diseases.

Core immune cell infiltration signatures identify molecular subtypes and promote precise checkpoint immunotherapy in cutaneous melanoma.

Yutao Wang, China Medical University, ChinaThe tumor microenvironment (TME) has been shown to impact the prognosis of tumors in patients including cutaneous melanoma (CM); however, not all components of TME are important. Given the aforementioned situation, the functional immune cell contents correlated with CM patient prognosis are needed to optimize present predictive models and reflect the overall situation of TME. We developed a novel risk score named core tumor-infiltrating immune cell score (cTICscore), which showed certain advantages over existing biomarkers or TME-related signatures in predicting the prognosis of CM patients. Furthermore, we explored a new gene signature named cTILscore-related module gene score (cTMGs), based on four identified TME-associated genes (GCH1, GZMA, PSMB8, and PLAAT4) showing a close correlation with the cTICscore, which was generated by weighted gene co-expression network analysis and least absolute shrinkage and selection operator analysis to facilitate clinical application. Patients with low cTMGs had significantly better overall survival (OS, P = 0.002,< 0.001, = 0.002, and = 0.03, respectively) in the training and validating CM datasets. In addition, the area under the curve values used to predict the immune response in four CM cohorts were 0.723, 0.723, 0.754, and 0.792, respectively, and that in one gastric cohort was 0.764. Therefore, the four-gene signature, based on cTICscore, might improve prognostic information, serving as a predictive tool for CM patients receiving immunotherapy.cutaneous melanoma, tumor microenvironment, prognosis, immunotherapy, cTICscore.

Cuproptosis-Related Risk Score Predicts Prognosis and Characterizes the Tumor Microenvironment in Hepatocellular Carcinoma.

Aims: Cuproptosis is a recently identified form of programmed cell death; however, its role in hepatocellular carcinoma (HCC) remains unclear. Methods: A set of bioinformatic tools was integrated to analyze the expression and prognostic significance of ferredoxin 1 (FDX1), the key regulator of cuproptosis. A cuproptosis-related risk score (CRRS) was developed via correlation analyses, least absolute shrinkage and selection operator (LASSO) Cox regression, and multivariate Cox regression. The metabolic features, mutation signatures, and immune profile of CRRS-classified HCC patients were investigated, and the role of CRRS in therapy guidance was analyzed. Results: FDX1 was significantly downregulated in HCC, and its high expression was associated with longer survival time. HCC patients in the high-CRRS group showed a significantly lower overall survival (OS) and enriched in cancer-related pathways. Mutation analyses revealed that the high-CRRS HCC patients had a high mutational frequency of some tumor suppressors such as tumor protein P53 (TP53) and Breast-cancer susceptibility gene 1 (BRCA1)-associated protein 1 (BAP1) and a low frequency of catenin beta 1 (CTNNB1). Besides, HCC patients with high CRRS showed an increase of protumor immune infiltrates and a high expression of immune checkpoints. Moreover, the area under the curve (AUC) values of CRRS in predicting the efficiency of sorafenib and the non-responsiveness to transcatheter arterial chemoembolization (TACE) in HCC patients reached 0.877 and 0.764, respectively. Significance: The cuproptosis-related signature is helpful in prognostic prediction and in guiding treatment for HCC patients.

Downregulation of NEDD4L by EGFR signaling promotes the development of lung adenocarcinoma.

Cumulative evidence indicates that the abnormal regulation of the NEDD4 family of E3-ubiquitin ligases participates in the tumorigenesis and development of cancer. However, their role in lung adenocarcinoma (LUAD) remains unclear. This study comprehensively analyzed the NEDD4 family in LUAD data sets from public databases and found only NEDD4L was associated with the overall survival of LUAD patients. Gene set enrichment analysis (GSEA) indicated that NEDD4L might be involved in the regulation of mTORC1 pathway. Both cytological and clinical assays showed that NEDD4L inhibited the activity of the mTOR signaling pathway. In vivo and in vitro experiments showed that NEDD4L could significantly inhibit the proliferation of LUAD cells. In addition, this study also found that the expression of NEDD4L was regulated by EGFR signaling. These findings firstly revealed that NEDD4L mediates an interplay between EGFR and mTOR pathways in LUAD, and suggest that NEDD4L held great potential as a novel biomarker and therapeutic target for LUAD.

Tumor purity as a prognosis and immunotherapy relevant feature in cervical cancer.

BACKGROUND: Tumor purity plays a vital role in the biological process of solid tumors, but its function in gynecologic cancers remains unclear. This study explored the correlation between tumor purity and immune function of gynecological cancers and its reliability as a prognostic indicator of immunotherapy. METHODS: Gynecological cancer-related datasets were downloaded from The Cancer Genome Atlas (TCGA). Tumor purity was calculated by the ESTIMATE algorithm. A LASSO Cox regression analysis was performed to construct the risk score model. A Kaplan-Meier Plotter was used to explore the relationships between tumor purity and cancer prognosis. We performed the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Set Enrichment Analysis (GSEA) to explore the pathways in the subgroups. A nomogram was used to quantitatively assess the cancer prognosis. RESULTS: Tumor purity was negatively correlated with B cell infiltration in cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC). Approximately 420 genes were positively associated with B cell infiltration and CESC prognosis and were enriched in immune-related signaling pathways. There were 11 key genes used to construct a risk score model. The low-risk group had a higher immune score and better prognosis than the high-risk group. A nomogram based on risk score, T stage, and clinical-stage had good predictive value in quantitatively evaluating CESC prognosis. CONCLUSIONS: This study is the first to reveal the correlation between tumor purity and immunity in CESC and suggests that low-risk patients may be more sensitive to immunotherapy. This provides a theoretical basis for the clinical treatment of CESC.

Integrated bioinformatics analysis of the NEDD4 family reveals a prognostic value of NEDD4L in clear-cell renal cell cancer.

The members of the Nedd4-like E3 family participate in various biological processes. However, their role in clear cell renal cell carcinoma (ccRCC) is not clear. This study systematically analyzed the Nedd4-like E3 family members in ccRCC data sets from multiple publicly available databases. NEDD4L was identified as the only NEDD4 family member differentially expressed in ccRCC compared with normal samples. Bioinformatics tools were used to characterize the function of NEDD4L in ccRCC. It indicated that NEDD4L might regulate cellular energy metabolism by co-expression analysis, and subsequent gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. A prognostic model developed by the LASSO Cox regression method showed a relatively good predictive value in training and testing data sets. The result revealed that NEDD4L was associated with biosynthesis and metabolism of ccRCC. Since NEDD4L is downregulated and dysregulation of metabolism is involved in tumor progression, NEDD4L might be a potential therapeutic target in ccRCC.

Bcl-2 Associated Athanogene 2 (BAG2) is Associated With Progression and Prognosis of Hepatocellular Carcinoma: A Bioinformatics-Based Analysis.

Background: Bcl-2 associated athanogene2 (BAG2) is reported to act as an oncogene or a tumor-suppressor in tumors in a context-dependent way; however, its function in hepatocellular carcinoma (HCC) remains unclear. Methods: Immunohistochemistry (IHC) staining, cell counting kit-8 (CCK-8) assay, apoptotic assay, cell invasion assay and a set of bioinformatics tools were integrated to analyze the role of BAG2 in hepatocellular carcinoma. Results: BAG2 was significantly up-regulated in HCC. Prognostic analysis indicated that HCC patients with high expression of BAG2 had significantly shorter overall survival, progression free survival and disease specific survival. Besides, silencing BAG2 in HCC cells impaired cell proliferation, facilitated apoptosis and repressed invasion of the cells. Bioinformatics analysis showed that BAG2 might regulate ribosome biogenesis in HCC. Conclusion: This study revealed that the up-regulated BAG2 in HCC was associated with a worse prognosis and might favor the progression of the disease.

Development and Validation of a CD8+ T Cell Infiltration-Related Signature for Melanoma Patients.

Aim: Immunotherapy shows efficacy in only a subset of melanoma patients. Here, we intended to construct a risk score model to predict melanoma patients' sensitivity to immunotherapy. Methods: Integration analyses were performed on melanoma patients from high-dimensional public datasets. The CD8+ T cell infiltration related genes (TIRGs) were selected via TIMER and CIBERSORT algorithm. LASSO Cox regression was performed to screen for the crucial TIRGs. Single sample gene set enrichment analysis (ssGSEA) and ESTIMATE algorithm were used to evaluate the immune activity. The prognostic value of the risk score was determined by univariate and multivariate Cox regression analysis. Results: 184 candidate TIRGs were identified in melanoma patients. Based on the candidate TIRGs, melanoma patients were classified into three clusters which were characterized by different immune activity. Six signature genes were further screened out of 184 TIRGs and a representative risk score for patient survival was constructed based on these six signature genes. The risk score served as an indicator for the level of CD8+ T cell infiltration and acted as an independent prognostic factor for the survival of melanoma patients. By using the risk score, we achieved a good predicting result for the response of cancer patients to immunotherapy. Moreover, pan-cancer analysis revealed the risk score could be used in a wide range of non-hematologic tumors. Conclusions: Our results showed the potential of using signature gene-based risk score as an indicator to predict melanoma patients' sensitivity to immunotherapy.

Over-expressed RHEB promotes the progression of pancreatic adenocarcinoma.

AIMS: Mammalian/mechanistic target of rapamycin (mTOR) is essential in the progression of pancreatic adenocarcinoma (PAAD). But the role of Ras homolog enriched in brain (RHEB), a key activator of mTORC1, is unclear in this disease. This work aims to clarify the function of RHEB in PAAD. MATERIALS AND METHODS: A pan-cancer analysis of RHEB was conducted by using data from several public available databases. Immunohistochemical (IHC) staining on a tissue microarray was used to validate the expression of RHEB in PAAD. In vitro experiments were conducted to explore the function of RHEB in the disease. An integrated bioinformatics tools were used to understand the mechanism of RHEB and construct a RHEB-related prognostic signature. KEY FINDINGS: RHEB was significantly overexpressed in PAAD and high expression of the gene was associated with poor prognosis. RHEB promoted proliferation, migration and invasion of pancreatic cancer cells. Gene set enrichment analysis (GSEA) showed that RHEB participated in cell cycle progression and WNT signaling pathway. A RHEB-related prognostic signature was developed, and PAAD patients with high risk score had a significantly shorter overall survival. SIGNIFICANCE: RHEB was up-regulated in PAAD and might be a useful therapeutic target.

Multi-Omics Analysis of Anlotinib in Pancreatic Cancer and Development of an Anlotinib-Related Prognostic Signature.

Aberrant regulation of angiogenesis involves in the growth and metastasis of tumors, but angiogenesis inhibitors fail to improve overall survival of pancreatic cancer patients in previous phase III clinical trials. A comprehensive knowledge of the mechanism of angiogenesis inhibitors against pancreatic cancer is helpful for clinical purpose and for the selection of patients who might benefit from the inhibitors. In this work, multi-omics analyses (transcriptomics, proteomics, and phosphoproteomics profiling) were carried out to delineate the mechanism of anlotinib, a novel angiogenesis inhibitor, against pancreatic cancer cells. The results showed that anlotinib exerted noteworthy cytotoxicity on pancreatic cancer cells. Multi-omics analyses revealed that anlotinib had a profound inhibitory effect on ribosome, and regulated cell cycle, RNA metabolism and lysosome. Based on the multi-omics results and available data deposited in public databases, an anlotinib-related gene signature was further constructed to identify a subgroup of pancreatic cancer patients who had a dismal prognosis and might be responsive to anlotinib.

Design, synthesis and evaluation of dihydrotriazine derivatives-bearing 5-aryloxypyrazole moieties as antibacterial agents.

In the present investigation, a series of dihydrotriazine derivatives-bearing 5-aryloxypyrazole moieties were synthesized and their structures were confirmed by different spectral tools. The biological evaluation in vitro revealed that some of the target compounds exerted good antibacterial and antifungal activity in comparison with the reference drugs. Among these novel hybrids, compound 10d showed the most potent activity with minimum inhibitory concentration values (MIC) of 0.5 µg/mL against S. aureus 4220, MRSA 3506 and E. coli 1924 strain. The cytotoxic activity of the compounds 6d, 6m, 10d and 10g was assessed in MCF-7 and HeLa cells. Growth kinetics study showed significant inhibition of bacterial growth when treated with different conc. of 10d. In vitro enzyme study implied that compound 10d exerted its antibacterial activity through DHFR inhibition. Moreover, significant inhibition of biofilm formation was observed in bacterial cells treated with MIC conc. of 10d as visualized by SEM micrographs. Twenty-nine target compounds were designed, synthesized and evaluated in terms of their antibacterial and antifungal activities.

Prognostic Factors of Colorectal Cancer: A Comparative Study on Patients With or Without Liver Metastasis.

BACKGROUND: Radical or palliative surgery with subsequent adjuvant therapy is the routine treatment for stage II/III colorectal cancer(CRC) and some stage IV CRC patients. This study aimed to clarify the prognostic clinicopathological and genetic factors for these patients. METHODS: Fifty-five stage II-IV CRC patients undergoing surgery and adjuvant therapy were recruited, including patients without liver metastasis(5 at stage II, 21 at stage III) and with liver metastasis(29 at stage IV). Genetic alterations of the primary cancer tissues were investigated by whole exome sequencing(WES). Patients were followed up to 1652 days(median at 788 days). RESULTS: The mutational landscape of primary CRC tissue of patients with or without liver metastasis was largely similar, although the mutational frequency of TRIM77 and TCF7L2 was significantly higher in patients with liver metastasis. Several main driver gene co-mutations, such as TP53-APC, APC-KRAS, APC-FRG1, and exclusive mutations, such as TP53-CREBBP, were found in patients with liver metastasis, but not in patients without liver metastasis. No significant difference was found between the two groups in aberrant pathways. If stage II-IV patients were studied altogether, relapse status, SUPT20HL1 mutations, Amp27_21q22.3 and Del8_10q23.2 were independent risk factors(P<0.05). If patients were divided into two groups by metastatic status, surgery types and Amp6_20q13.33 were independent risk factors for patients without liver metastasis(P<0.05), while TRIM77 mutations were the only independent risk factor for patients with liver metastasis(P<0.05). CONCLUSIONS: Surgery types and Amp6_20q13.33 were independent risk factors for CRC patients without liver metastasis, and TRIM77 mutations were the independent risk factor for CRC patients with liver metastasis.

Systematic analysis of the ABC transporter family in hepatocellular carcinoma reveals the importance of ABCB6 in regulating ferroptosis.

AIMS: ATP-binding cassette (ABC) transporters constitute one of the largest families of membrane proteins in most organisms; however, their functions in hepatocellular carcinoma (HCC) remain unclear. MAIN METHODS: A set of bioinformatic tools was integrated to analyze the expression of 49 members of the ABC transporter family. The function of members which had prognostic values in HCC was explored by gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. KEY FINDINGS: ABCA8 and ABCA9 were significantly down-regulated in HCC. Prognostic analysis indicated that HCC patients with low expression of ABCA8 and ABCA9 had significantly shorter survival time. On the contrary, ABCB6 was over-expressed in the disease and high expression of ABCB6 was associated with worse prognosis. Co-expression analysis, and subsequently GO and KEGG analysis indicated that ABCA8 and ABCA9 might participate in the catabolic processes of multiple metabolites, while ABCB6 might regulate ferroptosis. SIGNIFICANCE: This study reveals a previously unrecognized function of ABCB6 in HCC, by regulating ferroptosis. Since ABCB6 is over-expressed in HCC and ferroptosis involves in cancer development, ABCB6 might be a promising therapeutic target in the disease.

Biodistribution studies of boronophenylalanine in different types of skin melanoma.

A study of the 10B-enriched Boronophenylalanine-fructose complex(10BPA-F) infusion procedure in potential BNCT patients, including three skin melanomas of extremities, was performed. 10B concentration in tumor(T), blood(B), skin(S) were measured to determine tumor/blood(T/B) and skin/blood(S/B) ratios. T/B ratio for three melanoma patients was in the range 1.48-3.82(average 2.56 ± 0.69). S/B ratio was in the range 0.81-1.99(average 1.29 ± 0.35). Results showed that T/B ratio of nodular metastasis melanoma was higher than superficial spreading melanoma. 10B concentration in skin was higher than blood, which was helpful to avoid over-dose in normal skin.

Synthesis, biological evaluation of benzothiazole derivatives bearing a 1,3,4-oxadiazole moiety as potential anti-oxidant and anti-inflammatory agents.

Twenty benzothiazole derivatives bearing a 1,3,4-oxadiazole moiety were synthesized and evaluated for their anti-oxidant and anti-inflammatory activities. Among these compounds, 8h and 8l were appeared to have high radical scavenging efficacies as 0.05 ± 0.02 and 0.07 ± 0.03 mmol/L of IC50 values in ABTS+ bioassay, respectively. In anti-inflammatory tests, compound 8h displayed good activity with 57.35% inhibition after intraperitoneal administration, which was more potent than the reference drug (indomethacin). Molecular modeling studies were performed to investigate the binding mode of the representative compound 8h into COX-2 enzyme. In vitro enzyme study implied that compound 8h exerted its anti-inflammatory activity through COX-2 inhibition.

Integrated Analysis of the ETS Family in Melanoma Reveals a Regulatory Role of ETV7 in the Immune Microenvironment.

The ETS family modulates immune response and drug efficiency to targeted therapies, but their role in melanoma is largely unclear. In this study, the ETS family was systematically analyzed in multiple public data sets. Bioinformatics tools were used to characterize the function of ETV7 in melanoma. A prognostic model was constructed using the LASSO Cox regression method. We found that ETV7 was the only differentially expressed gene with significant prognostic relevance in melanoma. Enrichment analysis of seven independent data sets indicated ETV7 participation in various immune-related pathways. ETV7 particularly showed a strong positive correlation with CD8+ T cell infiltration. The prognostic model based on ETV7 and its hub genes showed a relatively good predictive value in training and testing data sets. Thus, ETV7 can potentially regulate the immune microenvironment in melanoma.

Development and Validation of a Combined Ferroptosis and Immune Prognostic Classifier for Hepatocellular Carcinoma.

BACKGROUND: Immunotherapy and sorafenib exert anti-tumor effects via ferroptosis, but reliable biomarkers for the individual treatment and prognosis prediction of hepatocellular carcinoma (HCC) based on the ferroptosis and immune status remain lacking. METHODS: Ferroptosis-related genes (FRGs) were identified by downloading data from FerrDb and by searching and reading original articles from PubMed. Immune-related genes (IRGs) were downloaded from ImmPort. Prognostic FRGs and IRGs in the GSE14520 (n = 220) and The Cancer Genome Atlas (TCGA, n = 365) datasets were identified. Least absolute shrinkage and selection operator (LASSO) Cox regression and multivariate Cox regression were used for model construction. Ferroptosis expression profiles, the infiltration of immune cells, and the somatic mutation status were analyzed and compared. RESULTS: Twenty-seven prognostic ferroptosis- and immune-related signatures were included to construct a comprehensive index of ferroptosis and immune status (CIFI). A subgroup of patients was identified as having a high CIFI value, which was associated with a worse prognosis. This subgroup of patients had significantly up-regulated expressions of many suppressors of ferroptosis and higher fractions of immunosuppressive cells, such as cancer-associated fibroblasts (CAFs) and myeloid-derived suppressor cells (MDSCs). Notably, somatic mutation analysis indicated that high-CIFI patients had higher levels of tumor heterogeneity and higher mutation frequencies of genes like TP53. CONCLUSION: In this work, a novel prognostic classifier was developed based on ferroptosis- and IRGs in HCC, and this classifier could be used for prognostic prediction and the selection of patients for immunotherapies and targeted therapies.