Background: The incidence of clear cell renal cell carcinoma (ccRCC) is increasing worldwide, contributing to 70-85% of kidney cancer cases. Ferroptosis is a novel type of programmed cell death and could predict prognoses in cancers. Here, we developed a ferroptosis-related long non-coding RNA (FRlncRNA) signature to improve the prognostic prediction of ccRCC. Methods: The transcriptome profiles of FRlncRNAs and clinical data of ccRCC were obtained from The Cancer Genome Atlas and ICGC databases. Patients were randomly assigned to training cohorts, testing cohorts, and overall cohorts. The FRlncRNA signature was constructed by Lasso regression and Cox regression analysis, and Kaplan-Meier (K-M) analysis was used to access the prognosis of each group. The accuracy of this signature was evaluated by the receiver operating characteristic (ROC) curve. The visualization of functional enrichment was carried out by the gene set enrichment analysis (GSEA). Internal and external datasets were performed to verify the FRlncRNA signature. Results: A FRlncRNA signature comprising eight lncRNAs (AL590094.1, LINC00460, LINC00944, AC024060.1, HOXB-AS4, LINC01615, EPB41L4A-DT, and LINC01550) was identified. Patients were divided into low- and high-risk groups according to the median risk score, in which the high-risk group owned a dramatical shorter survival time than that of the low-risk group. Through ROC analysis, it was found that this signature had a greater predictive capability than traditional evaluation methods. The risk score was an independent risk factor for overall survival suggested by multivariate Cox analysis (HR = 1.065, 95%CI = 1.036-1.095, and p < 0.001). We constructed a clinically predictive nomogram based on this signature and its clinical features, which is of accurate prediction about the survival rate of patients. The GSEA showed that primary pathways were the P53 signaling pathway and tumor necrosis factor-mediated signaling pathway. The major FRlncRNAs (LINC00460, LINC00944, LINC01550, and EPB41L4A-DT) were verified with the prognosis of ccRCC in the GEPIA and K-M Plotter databases. Their major target genes (BNIP3, RRM2, and GOT1) were closely related to the stage, grade, and survival outcomes of ccRCC by the validation of multiple databases. Additionally, we found two groups had a significant distinct pattern of immune function, immune checkpoint, and immune infiltration, which may lead to different survival benefits. Conclusions: The FRlncRNA signature was accurate and act as reliable tools for predicting clinical outcomes and the immune microenvironment of patients with ccRCC, which may be molecular biomarkers and therapeutic targets.

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