TIPE Inhibits Ferroptosis in Colorectal Cancer Cells by Regulating MGST1/ALOX5

Abstract TIPE is a protein highly expressed in various cancers that promotes ferroptosis in colorectal cancer cells. Ferroptosis is a nonapoptotic cell death caused by lipid peroxidation, and microsomal glutathione transferase 1 (MGST1) is a critical enzyme that resists lipid peroxidation. This study explored how TIPE regulates MGST1 expression to inhibit ferroptosis and promote colorectal cancer proliferation. TIPE was highly expressed in colorectal cancer tissues and positively correlated with the proliferation of human colorectal cancer cells. We measured levels of reactive oxygen species and lipid reactive oxygen species in colorectal cancer cells with differential expression of TIPE and detected ferroptosis using transmission electron microscopy. Bioinformatics analysis revealed a positive correlation of expression patterns between TIPE and MGST1 in colorectal cancer. TIPE regulated the expression of MGST1 by activating the phosphorylation of ERK1/2. Coimmunoprecipitation revealed binding between MGST1 and ALOX5. This binding inhibited the phosphorylation of ALOX5, inhibiting ferroptosis and promoting the proliferation of colorectal cancer cells. A tumor formation experiment in nude mice supported our findings that TIPE regulates the proliferation of colorectal cancer by regulating ferroptosis. Implications: TIPE inhibits colorectal cancer ferroptosis via an MGST1–ALOX5 interaction to promote colorectal cancer proliferation. These findings suggest future colorectal cancer treatment strategies.