Malic enzyme 1 is a prognostic factor and a therapeutic target to enhance progestin sensitivity in endometrial cancer

Abstract Purpose Fertility-sparing progestin therapy with medroxyprogesterone acetate (MPA) is an important option for young patients with endometrioid endometrial carcinoma (EEC); however, resistance limits its efficacy. Malic enzyme 1 (ME1) provides NADPH for biosynthesis and redox homeostasis, but its roles in EEC and progestin sensitivity remain unclear. We investigated the prognostic significance of ME1 and whether its inhibition enhances MPA sensitivity in EEC. Methods ME1 protein expression was assessed by immunohistochemistry in specimens from 172 patients with EEC and 6 normal endometria, and its association with progression-free survival (PFS) was analyzed. In vitro, ME1 was suppressed by siRNA-mediated knockdown and a pharmacological inhibitor in EEC cell lines. Proliferation, progesterone receptor (PR) expression, and reactive oxygen species (ROS) were evaluated after ME1 suppression alone or in combination with MPA; the combination was also tested in a xenograft model. Results ME1 expression was significantly higher in EEC than in normal endometrium, and high ME1 expression (H-score ≥ 75.66) was independently associated with shorter PFS (HR 1.89, 95% CI 1.07–3.34, P = 0.028). ME1 suppression inhibited proliferation in all EEC cell lines. In PR-positive Ishikawa cells, ME1 inhibition increased ROS, upregulated PR, and synergized with MPA (maximum ΔBliss score, 0.51). In vivo, the ME1 inhibitor plus MPA suppressed tumor growth more than either agent alone, without apparent toxicity. Conclusion ME1 overexpression is associated with poor prognosis in EEC. ME1 inhibition synergistically enhances MPA sensitivity by promoting ROS accumulation and upregulating PR, supporting ME1 as a candidate target for improving progestin-based fertility-sparing therapy in EEC.