Epithelial ovarian cancer(EOC)is one of the leading causes of death from gynecologic cancers and peri-toneal dissemination is the major cause of death in patients with EOC.Although the loss of 4.1 N is associ-ated with increased risk of malignancy,its association with EOC remains unclear.To explore the underlying mechanism of the loss of 4.1 N in constitutive activation of epithelial-mesenchymal transition(EMT)and matrix-detached cell death resistance,we investigated samples from 268 formalin-fixed EOC tissues and performed various in vitro and in vivo assays.We report that the loss of 4.1 N correlated with progress in clinical stage,as well as poor survival in EOC patients.The loss of 4.1 N induces EMT in adherent EOC cells and its expression inhibits anoikis resistance and EMT by directly binding and accelerating the degradation of 14-3-3 in suspen-sion EOC cells.Furthermore,the loss of 4.1 N could increase the rate of entosis,which aggravates cell death resistance in suspension EOC cells.Moreover,xeno-graft tumors in nude mice also show that the loss of 4.1 N can aggravate peritoneal dissemination of EOC cells.Single-agent and combination therapy with a ROCK inhibitor and a 14-3-3 antagonist can reduce tumor spread to varying degrees.Our results not only define the vital role of 4.1 N loss in inducing EMT,anoikis resistance,and entosis-induced cell death resistance in EOC,but also suggest that individual or combined application of 4.1 N,14-3-3 antagonists,and entosis inhibitors may be a promising therapeutic approach for the treatment of EOC.