Identification of ACSL4 as a biomarker and contributor of ferroptosis in clear cell renal cell carcinoma

Abstract

Background: Acyl-CoA Synthetase Long-Chain Family Member 4 (ACSL4) has been linked to the ferroptosis process and is implicated in the pathogenesis of tumors. Nevertheless, neither the expression levels of ACSL4 nor its prognostic significance in clear cell renal cell carcinoma (ccRCC) is completely understood at this time.Methods: Predictions of the ACSL4 mRNA expression in ccRCC and its link to ccRCC prognosis were made based on data from the Oncomine and The Cancer Genome Atlas (TCGA) databases. Through the use of real-time polymerase chain reaction (PCR), we ascertained the levels of ACSL4 expression in human RCC samples. Analyses of the link between ACSL4 expression and the survival of ccRCC patients were undertaken using the Kaplan-Meier (KM) plotter database. To study the function that ACSL4 plays in ferroptosis in ccRCC cell lines, either upregulation or knockdown of its expression was performed.Results: We found that the ACSL4 expression level was considerably down-modulated in ccRCC samples (P<0.001), which was in line with the analytical results of the Oncomine and TCGA database.The subsequent immunohistochemistry findings revealed that ACSL4 levels in ccRCC samples were much lower or not undetectable in contrast with those in normal samples. The level of differential ACSL4 expression was strongly associated with factors such as disease stages, gender, tumor grade, nodal invasion, and ccRCC subtypes (all P<0.001). According to the results of the survival analysis, the overall survival was satisfactory among ccRCC patients who had overexpressed ACSL4 (P=0.014). In cancer cells, ferroptosis sensitization may be restored by overexpressing ACSL4 via the process of transfection; however, increasing ferroptosis resistance can be achieved by suppressing ACSL4 expression through the use of shRNA.Protein ubiquitination could have a function in influencing the way that ACSL4-induced ferroptosis works mechanically.Conclusions: ACSL4, which is a mediator and monitor of ferroptosis, was lowered in expression in ccRCC and acted as a valuable diagnostic and prognostic biological marker, thus representing a novel promising treatment target for ccRCC.

ROS induced lipid peroxidation and their role in ferroptosis

“…These effects of the ferroptosis inducers and TRAIL to promote apoptosis were synergistic (Jiang et al, 2015;Xie et al, 2017;Lee et al, 2018;Lee et al, 2019). Cystatin protease cleaves acyl-CoA synthase long chain family member 4 (ACSL4) during bortezomib-induced apoptosis (Guo, 2022). Therefore, it is possible that the inactivation of ACSL4 during apoptosis prevents the insertion of PUFAs into the cell membrane, thereby reducing the capacity of cells to undergo ferroptosis.…”

MiRNA-449 family is epigenetically repressed and sensitizes to doxorubicin through ACSL4 downregulation in triple-negative breast cancer

“…Furthermore, higher proliferation rates, migration capacity, and colony formation have been observed upon ACSL4 overexpression in hepatocellular carcinoma and BC 66,69 . Contrarily, other studies correlate higher ACSL4 expression with better OS, RFS, and DFS, in lung adenocarcinoma, renal cell carcinoma, and colorectal cancer, among others [70][71][72][73] , which could be attributable to a tissue-speci c role of ACSL4. Based on our results, this study suggests an oncogenic role for ACSL4 in TNBC.…”

Novel Insight into Ferroptosis in Kidney Diseases

“…FRGsig may be a promising biomarker for predicting the success of angiogenesis-blocking medicines or immune checkpoint inhibitors in various subtypes of RCC, allowing for more accurate patient selection [103]. Moreover, ACSL4 has been identified as a biomarker and contributor to ferroptosis in ccRCC [104]. Five FI-DEGs (CCR4, CMTM3, IFITM1, MX2, and NR3C2) could be used as biomarkers to predict the outcome and diagnosis of KIRC in patients [105].…”