Ferroptosis, a distinct form of regulated cell death (RCD), has emerged as a promising approach for cancer treatment owing to its potential to inhibit tumor malignancy. Research indicates that non-coding RNAs (ncRNAs) regulate ferroptosis susceptibility in cancer cells through epigenetic modifications. ncRNAs play essential roles in cancer initiation, metastasis, and drug resistance. Findings indicate that small-molecule compounds (SMCs) target ncRNAs to regulate ferroptosis, providing new opportunities for precision cancer therapy. Therefore, this review aims to elucidate current molecular mechanisms underlying ncRNA-mediated ferroptosis regulation in cancer and investigate the potential of SMCs as therapeutic agents to modulate this process, offering a new strategy for precision in cancer treatment. This review also summarizes the innovative strategy of targeting ncRNAs with SMCs, a therapeutic approach for regulating ferroptosis and transforming the landscape of cancer treatment. Overall, it highlights a novel strategy for cancer therapy by pharmacologically targeting the ncRNA-ferroptosis axis with SMCs. Antioxid. Redox Signal. 43, 345–362.
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