Abstract High-grade serous ovarian cancer (HGSOC) remains highly lethal due to late diagnosis and the high frequency of chemoresistance, underscoring the need to identify new metabolic vulnerabilities that can be therapeutically targeted. This study investigates the mechanism through which inhibition of squalene epoxidase (SQLE), a rate-limiting enzyme that converts squalene to 2,3-epoxysqualene in the cholesterol biosynthesis pathway, suppresses ovarian cancer cell growth, and evaluates the therapeutic potential of the SQLE inhibitor NB-598. Using ovarian cancer cell lines cultured under cholesterol-replete and cholesterol-depleted conditions, we performed cell growth assays, western blot analysis of ER-stress signaling pathways, and apoptosis assays. NB-598 selectively inhibited ovarian cancer cell growth under cholesterol-depleted conditions, and this effect was fully reversed by cholesterol supplementation. Notably, inhibition of upstream HMG-CoA reductase with atorvastatin abolished NB-598-induced growth suppression, suggesting that NB-598 cytotoxicity does not stem from cholesterol deprivation but instead from the accumulation of squalene. Consistently, activation of ER-stress markers and rescue by JNK and p38 inhibitors implicate ER-stress signaling in NB-598-induced toxicity. Apoptosis was confirmed by cell-cycle analysis, Annexin V/PI staining, and western blotting, demonstrating increased sub-G1 populations, elevated early and late apoptotic cells, and cleavage of PARP and caspase-3 in NB-598-treated cells. Together, these findings identify squalene accumulation, rather than cholesterol depletion, as the primary driver of NB-598-induced cytotoxicity in ovarian cancer cells. This work establishes SQLE as a mechanistically defined metabolic target in ovarian cancer and provides a strong rationale for developing SQLE inhibitors as a novel therapeutic strategy. Citation Format: Cheng Chi, Lei Sun, Mahmuda Akter, Shuang Huang. SQLE inhibitor triggers ovarian cancer apoptosis by causing ER stress abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5694.
Chi et al. (Fri,) studied this question.