NSDHL as a regulator of lipid peroxidation and ER stress-mediated apoptosis in ovarian cancer.

Elevated expression of NAD(P)-dependent steroid dehydrogenase-like (NSDHL), a key enzyme in cholesterol biosynthesis, is associated with ovarian cancer progression and poor prognosis. However, the mechanisms underlying its tumor-promoting effects remain unclear. Here, we show that high NSDHL expression correlates with adverse clinical outcomes, particularly in aggressive subtypes such as high-grade serous ovarian cancer. NSDHL knockdown in cultured ovarian cancer cells reduced viability, triggered lipid peroxidation, and disrupted cholesterol and redox homeostasis, accompanied by elevated reactive oxygen species (ROS). Quantitative proteomic profiling revealed broad alterations in lipid metabolism, including suppression of fatty acid oxidation and PPARγ signaling, with upregulation of ACSL4 and downregulation of ACSL3. This shift toward polyunsaturated fatty acid (PUFA) enrichment enhanced susceptibility to oxidative stress but did not induce ferroptosis, owing to reduced intracellular iron levels. Notably, this paradoxical increase in lipid peroxidation despite iron deficiency contrasts with the classical ferroptosis model, in which iron is required to initiate and propagate lipid peroxidation, suggesting that NSDHL depletion uncouples oxidative membrane damage from canonical ferroptotic execution. Instead, apoptosis was mediated by lipid peroxidation–induced endoplasmic reticulum (ER) stress, as confirmed by upregulation of ER stress markers and activation of ER-specific caspases. Importantly, NSDHL depletion suppressed tumor growth and promoted ER stress–mediated apoptosis in ovarian cancer xenografts. These findings identify NSDHL as a key regulator of lipid metabolism and oxidative stress in ovarian cancer and highlight its potential as a therapeutic target.