Ferroptosis is an apoptosis-independent cell death pathway characterized by heightened lipid peroxidation, which shows promise for tumor suppression. Despite extensive research on long non-coding RNAs (LncRNAs) in ferroptosis, their role in colorectal cancer (CRC) remains underexplored. We investigated the upregulation of AC145207.5 and HNRNPC expression in CRC tissues through public dataset analysis and in-house validation, identifying them as having significant diagnostic potential. In vitro experiments including MTS assay, transwell, and colony formation, alongside in vivo studies using xenograft models, elucidated the synergistic carcinogenic role of the HNRNPC/AC145207.5 axis in promoting the malignant characteristics of CRC. Mechanistically, the m6A reader HNRNPC stabilized m6A-modified AC145207.5, contributing to its stabilization and upregulation. Consequently, AC145207.5 activated the Nrf2/GPX4 axis, resulting in increased GPX4 expression, inhibition of GPX4-mediated ferroptosis, and facilitation of CRC progression. Our findings underscore the clinical relevance of the HNRNPC/AC145207.5 axis in CRC and illuminate its regulatory role in ferroptosis, suggesting implications for targeted precision medicine in CRC.