Metabolome analysis identified exogenous cholesterol within lipid rafts that activate the Akt/mTOR signaling pathway in epithelial ovarian cancer

Sep 23, 2026

Epithelial ovarian cancer (EOC) is an aggressive malignancy with poor prognosis, and effective therapies remain limited. This research investigated how lipid metabolism supports EOC and assessed inhibition as a therapeutic strategy. High-fat diet (HFD)-fed mouse serum was analyzed by metabolomics to find lipids linked to EOC cell proliferation and to determine the activated signaling pathway. Cholesterol in lipid rafts activated Akt/mTOR, and disrupting it inactivated Akt/mTOR and suppressed EOC proliferation both in vitro and in vivo. Exogenous cholesterol promoted EOC growth via the lipid rafts–Akt/mTOR axis.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages12

Reading Time30 min

AccessFree to download

Introduction

Disease background and treatment challenges

Rationale for targeting lipid metabolism

Methods and analyses

Metabolome analysis strategy

Signaling pathway evaluation

Results

Identification of cholesterol in HFD-fed serum

Akt/mTOR activation by cholesterol in lipid rafts

Inhibition effects on EOC proliferation

What's New

Therapeutic potential of lipid raft-mediated cholesterol signaling

DOI: 10.1002/ijc.70401 RES EARCH A RTICLE Molec u la r C a n cer Bio logy Metabolome analysis identified exogenous cholesterol within lipid rafts that activate the Akt/mTOR signaling pathway in epithelial ovarian cancer Hitomi Sakaguchi-Mukaida 1 | Kosuke Hiramatsu 1 | Tatsuo Masuda 1 | Mamoru Kakuda 1 | Satoshi Nakagawa 1 | Tadashi Iwamiya 1 | Shinya Matsuzaki 1 | Tetsuji Naka 2 | Yutaka Ueda 1 | Tadashi Kimura 3 | Michiko Kodama 1 1Department of Obstetrics and Gynecology, The University of Osaka Graduate School of Medicine, Suita, Osaka, Japan 2Institute for Biomedical Sciences Molecular Pathophysiology, Iwate Medical University, Yahaba-cho, Iwate, Japan 3Sakai City Hospital Organization, Sakai, Osaka, Japan Correspondence Kosuke Hiramatsu, Department of Obstetricsand Gynecology, The University of Osaka Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka 565-0871, Japan. Email: [hiramatsu@gyne.med.osaka-u.ac.jp](hiramatsu@gyne.med.osaka-u.ac.jp) Abstract Epithelial ovarian cancer (EOC) is a highly aggressive malignancy with poor prognosis. Thus, new treatment options are needed. Recently, lipid metabolism in EOC has been highlighted. However, the specific lipid molecules activating lipid metabolism remain unclear. This study aimed to elucidate lipid metabolism in EOC and evaluate the potential of its inhibition as a therapeutic approach. We obtained high-fat diet (HFD)-fed mouse serum and performed metabolome analysis to identify lipid molecules contributing to cell proliferation of EOC. We also analyzed which signaling pathway was activated by the lipid molecule. Finally, we demonstrated the inhibition of lipid metabolism in EOC cells. HFD significantly promoted tumor growth of EOC cells in vivo, and HFD-fed mouse serum promoted EOC cell proliferation in vitro. Metabolome analysis identified cholesterol (C27 H46O) as a key molecule in HFD-fed mouse serum. Cholesterol (C27 H46O) activated the Akt/mTOR signaling pathway in vitro. Cholesterol (C27 H46O) is an important component of lipid rafts, and its inhibitor, which extracts cholesterol (C27 H46O) from lipid rafts, inactivated the Akt/mTOR signaling pathway and suppressed subsequent EOC cell proliferation. Exogenous cholesterol (C27 H46O) contributed to cell proliferation of EOC via the lipid rafts—Akt/mTOR signaling pathway, and its inhibition undoubtedly presents a novel therapeutic strategy for EOC. KEYWOR DS cholesterol, epithelial ovarian cancer, high-fat diet, lipid metabolism, metabolome analysis Abbreviations: BSA, bovine serum albumin; D-PBS, Dulbecco's phosphate-buffered saline; EGFR, epidermal growth factor receptor; EOC, epithelial ovarian cancer; FBS, fetal bovine serum; HCA, hierarchical cluster analysis; HCD, high-cholesterol (C27H46O) diet; HFD, high-fat diet; LC-TOFMS, liquid chromatography time-of-flight mass spectrometry; LDs, lipid droplets; LSR, lipolysisstimulated lipoprotein receptor; MβCD, methyl-β-cyclodextrin; ND, normal diet; PC, principal component; PCA, principal component analysis; PLS, partial least squares; RPMI, Roswell Park Memorial Institute; SC, subcutaneously; SCID, severe combined immunodeficient' mice; SDS-PAGE, sodium dodecyl sulfate-polyacrylamide gel electrophoresis; VIP score, variable importance in projection score. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. © 2026 The Author(s) . International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC. What's New? Epithelial ovarian cancer (EOC) is a severe malignancy with few effective treatment options. While the mechanisms remain unclear, changes in lipid metabolism may fuel tumor growth and EOC progression, offering a possible path for new treatments. Here, the authors examined seru

FAQs

What problem does the study address in epithelial ovarian cancer (EOC)?

EOC is highly aggressive and has few effective treatment options, with limited progress against recurrence and poor long-term survival.

How did the researchers identify lipids related to EOC cell proliferation?

They used metabolome analysis on high-fat diet (HFD)-fed mouse serum to find lipid molecules contributing to EOC cell proliferation.

Which signaling pathway did cholesterol activate, and what was the outcome of blocking it?

Cholesterol activated the Akt/mTOR signaling pathway in vitro; inhibition that disrupts cholesterol in lipid rafts inactivated Akt/mTOR and suppressed EOC cell proliferation.

Sep 23, 2026

Uploaded by วิน