This study provides the first mechanism through which CRM197 significantly reverses resistance to paclitaxel by modulating the NAC‐1/Gadd45gip1/Gadd45 pathway in paclitaxel‐resistant ovarian cancer cells and tissues, and HB‐EGF as a possible novel therapeutic target for patients with paclitaxel‐resistant ovarian cancer. This evidence concerns the gene GADD45GIP1 and ovarian cancer.