Recent statistics show that ovarian cancer is the first leading cause of gynecological cancer deaths [1]. The main reasons are related to the occult onset of the disease, late diagnosis, metastasis and chemo-resistance. The international ovarian cancer consensus recommends cytoreductive surgery with chemo-therapy as the primary treatment for ovarian cancer [2]. Many patients lose the opportunity for surgery since they are diagnosed at an advanced stage, and can only undergo chemo-therapy or targeted therapy. However, the application of clinical treatments is often constrained by the occurrence of resistance. It is therefore urgent to identify novel targets and develop new therapeutic strategies for ovarian cancer.

Metabolic reprogramming,a hallmark of cancer, involves the dysregulation of glucose, amino acid and lipid metabolism [[3], [4], [5]]. As to glucose metabolism in cancer cells, the Warburg effect is a well-known and pivotal component, whereby ATP and lactic acid are produced through aerobic glycolysis of glucose in the presence of oxygen. It has been suggested that targeting metabolic pathways is a viable and potential approach to enhance the therapeutic efficacy for cancer.

Squalene monooxygenase(SQLE), a key rate-limiting enzyme in cholesterol synthesis, converts squalene to 2,3-epoxy squalene [6]. Studies have shown that SQLE is aberrantly expressed in different tumors, acting as either a pro-tumor or a tumor suppressor gene. On one hand, downregulated SQLE favored temozolomide chemoresistance and promoted the invasive ability of glioma cells, and SQLE downregulation activated the β-catenin oncogenic pathway and inactivated the p53 tumor suppressor pathway in colon cancer cells [7,8]. On the other hand, SQLE drove cancer cell proliferation and accelerated colon carcinogenesis [9]. The expression profile and functional implications of SQLE in ovarian cancer remain largely understudied.

The pathogenesis of ovarian cancer is characterized by profound alterations in cellular metabolism and a distinct steroid hormone milieu. Cholesterol is an indispensable precursor for the biosynthesis of steroid hormones, including estrogen and progesterone that are primarily synthesized in the ovary [10]. The key rate-limiting enzyme in the cholesterol synthesis pathway, squalene epoxidase (SQLE), has been implicated in regulating ovarian reserve function [11]. Therefore, SQLE dysregulation is supposed to disrupt metabolic homeostasis and affect ovarian carcinogenesis. However, the specific role of SQLE in ovarian cancer progression and its mechanistic underpinnings are still poorly understood. Our previous investigations demonstrated that silencing SQLE abrogates the inhibitory effects of ginsenoside 20 (S)-Rg3 on the proliferation, invasion, and migration of ovarian cancer cells, supporting its tumor suppressive role [12]. In the present study, we further modulated SQLE expression pattern and examined its impact on cellular proliferation and metabolism in ovarian cancer. The findings clarify the mechanistic function of SQLE in ovarian cancer and highlight its potential as a metabolic target for therapeutic intervention.