LSR suppresses ferroptosis through alpha-tocopherol uptake and promotes tumor growth in gynecological cancers

Background Lipolysis-stimulated lipoprotein receptor (LSR) plays an important role in lipid uptake and is overexpressed in gynecologic cancers, where its high levels are correlated with unfavorable outcomes. However, the lipid metabolic mechanisms via LSR are not well understood. In this study, we investigated how LSR-dependent lipid uptake promotes tumor growth in gynecologic malignancies. Methods To explore the lipid metabolic mechanism mediated by LSR, we first demonstrated the effect of high-fat diet (HFD) on tumor growth of LSR-positive ovarian cancer in vivo, and compared the antitumor efficacy of anti-LSR antibody (Ab) between HFD-fed and normal diet (ND)-fed mice. Next, we assessed whether serum from HFD-fed mouse promotes proliferation of ovarian cancer cells in vitro. To identify lipid metabolites responsible for HFD-induced tumor promotion, we performed metabolomic analysis of HFD and ND mouse serum. Based on the identified metabolite, we further investigated its mechanistic contribution to tumor growth. Results HFD significantly promoted ovarian cancer growth (p < 0.05), and the antitumor effect of anti-LSR Ab was strongly effective in HFD-fed mouse in vivo (p < 0.05). HFD mouse serum also significantly enhanced cell proliferation of ovarian cancer cells in vitro (p < 0.05). Metabolomic analysis of HFD and ND mouse serum identified alpha-tocopherol (vitamin E) as the most discriminative metabolite. Alpha-tocopherol is a lipid-soluble antioxidant known to suppress ferroptosis; thus, we hypothesized that LSR-mediated alpha-tocopherol uptake inhibits ferroptosis in gynecological cancer cells. At first, we demonstrated that LSR knockdown (KD), using siRNA, significantly suppressed cell proliferation in endometrial and ovarian cancer cells (p < 0.05). LSR-KD also reduced GPX4 expression and increased reactive oxygen species (ROS) and lipid peroxidation, indicating enhanced ferroptosis sensitivity. Importantly, these effects were completely reversed by ferroptosis inhibitors but not by apoptosis or necroptosis inhibitors, suggesting that LSR inhibits ferroptosis specifically. In control endometrial and ovarian cancer cells, alpha-tocopherol supplementation restored cell proliferation (p < 0.05), GPX4 expression, and reduced ROS and lipid peroxidation under oxidative stress (H2O2 exposure). However, in LSR-KD cells, alpha-tocopherol did not show a rescue effect, consistent with impaired uptake via LSR. Conclusion LSR promotes tumor progression of gynecological cancers through alpha-tocopherol uptake, leading to ferroptosis suppression. Inhibition of alpha-tocopherol uptake via LSR may sensitize endometrial and ovarian cancers to ferroptosis-inducing treatments.