Renal cell carcinoma (RCC) represents a deadly type of genitourinary cancer, noted for its strong tendency to metastasize and its unfavorable outlook for patients. Despite significant advancements in targeted therapies and immunotherapies, tumor heterogeneity and therapeutic resistance remain formidable challenges, underscoring the urgent need for novel treatment strategies. Long non-coding RNAs (lncRNAs), once thought to be non-translatable, have recently been discovered to encode functional peptides that are crucial in the progression of tumors. In this study, we employed peptidomics to screen RCC tissues for lncRNA-encoded peptides and identified a novel peptide, TCL6148, encoded by TCL6. Through detailed bioinformatics assessments, laboratory experiments, and studies conducted in living organisms, we established that TCL6148 exerts anti-tumor effects by triggering ferroptosis in RCC cells through the GOT1/GPX4 signaling pathway. Mechanistically, TCL6148 facilitated the accumulation of Fe2+, increased levels of reactive oxygen species (ROS), and boosted lipid peroxidation, thus rendering RCC cells more susceptible to ferroptosis. Importantly, TCL6148 significantly enhanced the therapeutic effectiveness of sunitinib, indicating a promising combined approach for addressing drug resistance. In vivo experiments further validated the safety and efficacy of TCL6148 in suppressing RCC tumor growth. Collectively, our findings identify TCL6148 as a promising candidate for RCC treatment and provide novel insights into peptide-based therapeutic approaches, offering a potential avenue for improving RCC management.Copyright © 2024. Published by Elsevier B.V.