Intratumoral heterogeneity, including epithelial-mesenchymal transition (EMT), is one major cause of therapeutic resistance. The induction of ferroptosis, an iron-dependent death, has the potential in overcoming this resistance to traditional treatment modalities. However, the roles of distinct EMT phenotypes in ferroptosis remain an enigma. This study reports that 3D soft fibrin microenvironment confers colorectal cancer (CRC) cells hybrid EMT phenotype and high level of resistance to ferroptosis. The activation of histone acetylation and WNT/β-catenin signaling drives this EMT phenotypic transition, which promotes the defense of 3D CRCs against ferroptosis via glutathione peroxidases/ferritin signaling axis. Unexpectedly, E-cadherin knockout in 3D but not 2D CRCs mediates an integrin β