Abstract Background Ferroptosis is a newly defined form of programmed cell death that plays an important role in many cancers. However, ferroptosis-related lncRNAs (FRLs) involved in the regulation of colon cancer are not thoroughly understood. This study aimed to identify a prognostic FRL signature in colon cancer and explore its potential molecular function. Methods RNA-seq data and relevant clinical information were obtained from The Cancer Genome Atlas (TCGA) database, and a list of ferroptosis-related genes was extracted from the FerrDb website. Analysis of differentially expressed FRLs was performed using the ‘limma’ package in R software. By implementing coexpression analysis and univariate Cox analysis, we then identified prognostic FRLs. Using Cox regression analysis with the least absolute shrinkage and selection operator (LASSO) algorithm, we constructed a prognostic model based on 4 FRLs. We evaluated the prognostic power of this model using Kaplan–Meier (K-M) survival curve analysis and receiver operating characteristic (ROC) curve analysis. Moreover, the relationships between the signature and immune landscape, somatic mutation and drug sensitivity were explored. Finally, in vitro experiments were conducted to validate the functions of [49]AP003555.1 and AC000584.1. Results A 4-FRL signature was constructed. Two risk groups were classified based on the risk score calculated by this signature. The signature-based risk score exhibited a more powerful capacity for survival prediction than traditional clinicopathological features in colon patients. Additionally, we observed a significant difference in immune cells, such as CD4+ and CD8+ T cells and macrophages, between the two groups. Moreover, the high-risk group exhibited lower IC50 values for certain chemotherapy drugs, such as cisplatin, docetaxel, bleomycin or axitinib. Finally, the in vitro experiments showed that ferroptosis processes were suppressed after [50]AP003555.1 and AC000584.1 knockdown. Conclusion The proposed 4-FRL signature is a promising biomarker to predict clinical outcomes and therapeutic responses in colon cancer patients. Keywords: lncRNAs, ferroptosis, colorectal cancer, prognostic signature, immune microenvironment Introduction Colon cancer is the third most-diagnosed cancer and the second leading cause of cancer-related deaths in the world. Colon cancer seriously endangers human health ([51]1). According to the latest online epidemiological database, there were more than 1.9 million new colon cancer cases in 2020, and 0.9 million deaths were recorded in the same year ([52]2). The incidence rate and mortality rate have continuously risen in recent years. Even with the rapid development of cancer screening methods, many patients are diagnosed at an advanced stage with multiple symptoms, such as haematochezia or colonic obstruction ([53]2). However, there are only a few effective therapeutic targets for colon cancer patients ([54]3). Therefore, along with improvements in surgical treatments and chemoradiotherapies, it is also crucial and important to explore additional diagnostic biomarkers and possible therapeutic targets. Ferroptosis is a newly defined form of regulated cell death driven by loss of activity of the lipid repair enzyme glutathione peroxidase 4 (GPX4) and the subsequent accumulation of lipid-based reactive oxygen species (ROS), particularly lipid hydroperoxides ([55]4). This type of programmed cell death has been associated with carcinogenesis, intracerebral haemorrhage, degenerative diseases, stroke, and kidney degeneration ([56]5). Ferroptosis has unique morphological and bioenergetic features that can be easily distinguished from other types of programmed cell death, such as apoptosis or necrosis. Currently, inducing cancer ferroptosis is considered a promising therapeutic strategy, especially for drug-resistant cancers ([57]6). However, only a few ferroptosis-related therapeutic targets have been identified in colon cancer ([58]7–[59]9). Thus, further clinical sample-based screenings for ferroptosis-related genes (FRGs) are necessary for colon cancer diagnoses and treatments. Long noncoding RNA (lncRNA) refers to a type of noncoding RNA more than 200 nucleotides in length. LncRNAs constitute a major class of transcripts that are encoded by the genome but are mostly not translated into proteins ([60]10). In the past few decades, mounting evidence has shown that lncRNAs play key roles in regulating proliferation, metastasis, the cell cycle and programmed death in cancers ([61]11, [62]12). For example, we showed that lncRNA LUCAT1 could promote proliferation in colon cancer ([63]13). Recently, many researchers also found that lncRNAs, namely, LINC00618, could play a role in the ferroptosis process in cancer; this lncRNA was found to accelerate ferroptosis in an apoptosis-dependent manner ([64]14). Similarly, LINC00336 inhibits ferroptosis as a competing endogenous RNA in lung cancer ([65]15). Moreover, recent studies have demonstrated that lncRNA GABPB1-AS1 regulates erastin-induced ferroptosis with GABPB1 in HepG2 hepatocellular carcinoma ([66]16). However, current studies screening ferroptosis-related lncRNAs (FRLs) in colon cancer are limited. Accordingly, it is important to identify key FRLs with prognostic significance in colon cancer patients. In this study, we obtained RNA sequencing (RNA-seq) data from a colon adenocarcinoma (COAD) dataset and ultimately identified four differentially expressed FRLs and developed a prognostic model. Then, the mechanism of action of FRLs in colon cancer was further analysed by gene set enrichment analysis (GSEA), immunoinfiltration analysis and chemotherapy drug sensitivity analysis. Finally, we also tentatively validated the role of two FRLs with high expression in regulating ferroptosis in vitro. Our findings could help to predict the prognosis of colon cancer patients and provide references for clinical chemotherapy and