An inflammation‐associated ferroptosis signature optimizes the diagnosis, prognosis evaluation and immunotherapy options in hepatocellular carcinoma

Abstract

Inflammation and ferroptosis crosstalk complexly with immune microenvironment of hepatocellular carcinoma (HCC), thus affecting the efficacy of immunotherapy.Herein, our aim was to identify the inflammation-associated ferroptosis (IAF) biomarkers for contributing HCC. A total of 224 intersecting DEGs identified from different inflammation-and ferroptosis-subtypes were set as IAF genes. Seven of them including ADH4, APOA5, CFHR3, CXCL8, FTCD, G6PD and PON1 were used for construction of a risk model which classified HCC patients into two groups (high and low risk). HCC patients in the high-risk group exhibited shorter survival rate and higher immune score, and were predicted to have higher respond rate in immune checkpoint inhibition (ICI) therapy. Levels of the seven genes were significantly changed in HCC tissues in comparison to adjacent tissues. After inserting the gene expression into the risk model, we found that the risk model exhibited the higher diagnostic value for distinguish HCC tissues compared each single gene. Furthermore, HCC tissues from our research group with high-risk score exhibited more cases of microsatellite instability (MSI), heavier tumour mutational burden (TMB), higher expression level of PDL1 and cells with CD8. Knockdown of APOA5 reduced HCC cell proliferation combining with elevating inflammation and ferroptosis levels. In conclusion, we considered APOA5 maybe a novel target for suppressing HCC via simultaneously elevating inflammation and ferroptosis levels, and signature constructed by seven IAF genes including ADH4, APOA5, CFHR3, CXCL8, FTCD, G6PD and PON1 can act as a biomarker for optimising the diagnosis, prognosis evaluation and immunotherapy options in HCC patients.

Overexpression of tousled-like kinase 2 predicts poor prognosis in HBV-related hepatocellular carcinoma patients after radical resection

“…Then, we performed differential gene expression analysis in a cohort of HBV-related HCC patients from GSE 121248, and then four overlapped hub genes, SERPINA4, SLC22A7, CYP4A11, and PON1, were identified, which were significantly negatively correlated with TLK2. The above four hub genes were reported to be associated with the prognosis of patients with HCC (Yasui et al, 2014;Wu et al, 2019;Eun et al, 2019;Ruan et al, 2023). Therefore, we hypothesized that TLK2 and hub genes may have a reciprocal influence and consequently promote the occurrence and progression of HCC.…”

An immune signature to predict the prognosis of ATRX-wildtype glioma patients and guide immune checkpoint blockade therapy

“…A prognostic risk model was developed using multivariate Cox regression analysis with the Akaike information criterion. Kaplan-Meier survival analyses and receiver operating characteristic curve analyses were used for ATRX -wt and ATRX -mt glioma patients [ 35 ].…”

Exploring the relationship between anastasis and mitochondrial ROS-mediated ferroptosis in metastatic chemoresistant cancers: a call for investigation

“…Combinatorial therapy with immunotherapy and FSP1 inhibition typically mitigates hepatocellular carcinoma burden in vivo ( 296 ). Inflammation-associated ferroptosis biomarkers positively correlate with PD-L1 expression, high microsatellite instability, tumor mutational burden, and ICB response rates ( 297 ). Short-term methionine starvation synergistically promotes ferroptosis with CD8+ T cells by stimulating CHAC1 transcription, enhancing ICB therapy.…”