METTL16 antagonizes astaxanthin-induced ferroptosis in colorectal cancer cells

Background: Colorectal cancer (CRC) is one of the most common malignant tumors worldwide, characterized by difficulties in early diagnosis and frequent development of drug resistance to targeted therapies. Elucidating the molecular mechanisms of CRC pathogenesis and identifying novel molecular targets for early diagnosis and treatment are therefore of critical importance. Methyltransferase 16 (METTL16) plays crucial roles in CRC cell growth, development, and immune responses, making it a promising therapeutic target for CRC. Astaxanthin is a natural compound with numerous biological functions. This study aims to investigate the roles of METTL16 and astaxanthin in CRC, providing novel molecular targets and therapeutic directions for its treatment. Methods: Expression of METTL16 and 5'-aminolevulinate synthase 1 (ALAS1) in CRC was analyzed using The Cancer Genome Atlas (TCGA) data. Changes in cell viability, proliferation, migration, and invasion following treatment of CRC cells with different concentrations of astaxanthin were evaluated using the Cell Counting Kit-8 (CCK-8), scratch healing assay, and Transwell assay. Western blot analysis was employed to detect changes in the expression of ferroptosis-related proteins. Additionally, kit-based assays were used to measure alterations in Fe2+ and malondialdehyde (MDA) levels. Results: In vitro, astaxanthin demonstrates significant anti-tumor activity by inhibiting cell viability and proliferation. In vivo experiments using subcutaneous tumor-bearing mouse models further confirmed its ability to inhibit tumor growth and metastasis without apparent toxicity. Moreover, astaxanthin increases reactive oxygen species (ROS), MDA, and labile iron accumulation, thereby promoting ferroptosis, whereas METTL16 exhibits the opposite effect. Proteomics analysis further elucidated the relationship and mechanisms among METTL16, astaxanthin, and ferroptosis, revealing significant changes in several key proteins associated with ferroptosis-related pathways, mitochondrial energy metabolism, oxidative stress, and fatty acid metabolism. Conclusions: This study demonstrates that astaxanthin inhibits CRC cell growth and delineates its relationship and mechanisms with METTL16 and ferroptosis, providing a new direction for CRC treatment.