High‐dose progestins are the current standard of care for patients with endometrial cancer who have the desire to preserve fertility.[1a] However, progestin resistance commonly occurs.[8] Albeit multiple molecular pathways related to progestin resistance have been reported, no effective predictive biomarkers have been approved.[3b] In this study, we provide evidence that p38‐dependent IDH1 T77 phosphorylation confers progestin resistance by upregulating focal adhesion related gene expression (Figure 9). Here, IDH1 is linked to endometrial cancer.