Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Targeting cholesterol metabolism: a promising therapy strategy for cancer

Acta Pharmacologica Sinica volume 46, pages 2093–2104 (2025)Cite this article

Abstract

Cholesterol is a crucial structural component of cell membranes, playing a vital role in maintaining membrane fluidity and stability. Cholesterol metabolism involves four interconnected processes: de novo synthesis, uptake, efflux, and esterification. Disruptions in any of these pathways can lead to imbalances in cholesterol homeostasis, which are significantly associated with cancer progression. In recent years, traditional Chinese medicine (TCM) has emerged as a comprehensive therapeutic approach with multi-target and multi-pathway effects, demonstrating significant potential in regulating cholesterol metabolism. Research has shown that certain components of TCM can modulate enzymes, transport proteins, and signaling pathways involved in cholesterol metabolism, effectively interfering with survival and migration of cancer. These mechanisms highlight the unique advantages of TCM in inhibiting tumor progression. In this review we systematically describe the execution and regulation of the four key cholesterol metabolism processes, highlights the roles of critical proteins involved, and provides a comprehensive overview of natural products from TCM that modulate cholesterol metabolism. This review provides valuable insights for the development of novel drugs and cancer therapeutic strategies targeting cholesterol metabolism.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to the full article PDF.

USD 39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: The process of cholesterol metabolism.
Fig. 2: Mechanisms of action of natural products targeting cholesterol biosynthesis in cancer.
Fig. 3: Mechanisms of action of natural products targeting cholesterol uptake in cancer.
Fig. 4: Mechanisms of action of natural products targeting cholesterol efflux and esterification in cancer.

Similar content being viewed by others

References

  1. Patel KK, Kashfi K. Lipoproteins and cancer: The role of HDL-C, LDL-C, and cholesterol-lowering drugs. Biochem Pharmacol. 2022;196:114654.

    Article  CAS  PubMed  Google Scholar 

  2. Schallreuter KU, Hasse S, Rokos H, Chavan B, Shalbaf M, Spencer JD, et al. Cholesterol regulates melanogenesis in human epidermal melanocytes and melanoma cells. Exp Dermatol. 2009;18:680–8.

    Article  CAS  PubMed  Google Scholar 

  3. Wang Y, Zhou X, Lei Y, Chu Y, Yu X, Tong Q, et al. NNMT contributes to high metastasis of triple negative breast cancer by enhancing PP2A/MEK/ERK/c-Jun/ABCA1 pathway mediated membrane fluidity. Cancer Lett. 2022;547:215884.

    Article  CAS  PubMed  Google Scholar 

  4. Meng Y, Wang Q, Lyu Z. Cholesterol metabolism and tumor. Zhejiang Da Xue Xue Bao Yi Xue Ban. 2021;50:23–31.

    PubMed  PubMed Central  Google Scholar 

  5. Fitzgerald K, Redmond E, Harbor C. Statin-induced myopathy. Glob Adv Health Med. 2012;1:32–6.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Bell G, Thoma A, Hargreaves IP, Lightfoot AP. The role of mitochondria in statin-induced myopathy. Drug Saf. 2024;47:643–53.

    Article  CAS  PubMed  Google Scholar 

  7. Carrasco-Pozo C, Tan KN, Reyes-Farias M, De La Jara N, Ngo ST, Garcia-Diaz DF, et al. The deleterious effect of cholesterol and protection by quercetin on mitochondrial bioenergetics of pancreatic β-cells, glycemic control and inflammation: In vitro and in vivo studies. Redox Biol. 2016;9:229–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Choi YJ, Lee SJ, Kim HI, Lee HJ, Kang SJ, Kim TY, et al. Platycodin D enhances LDLR expression and LDL uptake via down-regulation of IDOL mRNA in hepatic cells. Sci Rep. 2020;10:19834.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Chen W, Zhang Q, Dai X, Chen X, Zhang C, Bai R, et al. PGC-1α promotes colorectal carcinoma metastasis through regulating ABCA1 transcription. Oncogene. 2023;42:2456–70.

    Article  CAS  PubMed  Google Scholar 

  10. Repa JJ, Mangelsdorf DJ. The role of orphan nuclear receptors in the regulation of cholesterol homeostasis. Annu Rev Cell Dev Biol. 2000;16:459–81.

    Article  CAS  PubMed  Google Scholar 

  11. Huang B, Song BL, Xu C. Cholesterol metabolism in cancer: mechanisms and therapeutic opportunities. Nat Metab. 2020;2:132–41.

    Article  PubMed  Google Scholar 

  12. Hua X, Yokoyama C, Wu J, Briggs MR, Brown MS, Goldstein JL, et al. SREBP-2, a second basic-helix-loop-helix-leucine zipper protein that stimulates transcription by binding to a sterol regulatory element. Proc Natl Acad Sci USA. 1993;90:11603–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Zhao Q, Lin X, Wang G. Targeting SREBP-1-mediated lipogenesis as potential strategies for cancer. Front Oncol. 2022;12:952371.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Cheng C, Geng F, Cheng X, Guo D. Lipid metabolism reprogramming and its potential targets in cancer. Cancer Commun. 2018;38:27.

    Article  Google Scholar 

  15. Xue L, Qi H, Zhang H, Ding L, Huang Q, Zhao D, et al. Targeting SREBP-2-regulated mevalonate metabolism for cancer therapy. Front Oncol. 2020;10:1510.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Guo C, Chi Z, Jiang D, Xu T, Yu W, Wang Z, et al. Cholesterol homeostatic regulator SCAP-SREBP2 integrates NLRP3 inflammasome activation and cholesterol biosynthetic signaling in macrophages. Immunity. 2018;49:842–856.e7.

    Article  CAS  PubMed  Google Scholar 

  17. Chen YY, Ge JY, Zhu SY, Shao ZM, Yu KD. Copy number amplification of ENSA promotes the progression of triple-negative breast cancer via cholesterol biosynthesis. Nat Commun. 2022;13:791.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Tang W, Zhou J, Yang W, Feng Y, Wu H, Mok MTS, et al. Aberrant cholesterol metabolic signaling impairs antitumor immunosurveillance through natural killer T cell dysfunction in obese liver. Cell Mol Immunol. 2022;19:834–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Plebanek MP, Xue Y, Nguyen YV, DeVito NC, Wang X, Holtzhausen A, et al. A lactate-SREBP2 signaling axis drives tolerogenic dendritic cell maturation and promotes cancer progression. Sci Immunol. 2024;9:eadi4191.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Wei S, Liu L, Chen Z, Yin W, Liu Y, Ouyang Q, et al. Artesunate inhibits the mevalonate pathway and promotes glioma cell senescence. J Cell Mol Med. 2020;24:276–84.

    Article  CAS  PubMed  Google Scholar 

  21. Xiao MY, Pei WJ, Li S, Li FF, Xie P, Luo HT, et al. Gypenoside L inhibits hepatocellular carcinoma by targeting the SREBP2-HMGCS1 axis and enhancing immune response. Bioorg Chem. 2024;150:107539.

    Article  CAS  PubMed  Google Scholar 

  22. Mok EHK, Leung CON, Zhou L, Lei MML, Leung HW, Tong M, et al. Caspase-3-induced activation of SREBP2 drives drug resistance via promotion of cholesterol biosynthesis in hepatocellular carcinoma. Cancer Res. 2022;82:3102–15.

    Article  CAS  PubMed  Google Scholar 

  23. Kim YS, Lee YM, Oh TI, Shin DH, Kim GH, Kan SY, et al. Emodin sensitizes hepatocellular carcinoma cells to the anti-cancer effect of sorafenib through suppression of cholesterol metabolism. Int J Mol Sci. 2018;19:3127.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Fan K, Huang H, Zhao Y, Xie T, Zhu ZY, Xie ML. Osthole increases the sensitivity of liver cancer to sorafenib by inhibiting cholesterol metabolism. Nutr Cancer. 2022;74:3640–50.

    Article  CAS  PubMed  Google Scholar 

  25. Migita T, Ruiz S, Fornari A, Fiorentino M, Priolo C, Zadra G, et al. Fatty acid synthase: a metabolic enzyme and candidate oncogene in prostate cancer. J Natl Cancer Inst. 2009;101:519–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Pokhrel RH, Acharya S, Ahn JH, Gu Y, Pandit M, Kim JO, et al. AMPK promotes antitumor immunity by downregulating PD-1 in regulatory T cells via the HMGCR/p38 signaling pathway. Mol Cancer. 2021;20:133.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Zhang Z, Yang J, Liu R, Ma J, Wang K, Wang X, et al. Inhibiting HMGCR represses stemness and metastasis of hepatocellular carcinoma via Hedgehog signaling. Genes Dis. 2024;11:101285.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Jiang W, Hu JW, He XR, Jin WL, He XY. Statins: a repurposed drug to fight cancer. J Exp Clin Cancer Res. 2021;40:241.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Basavaraj P, Ruangsai P, Hsieh PF, Jiang WP, Bau DT, Huang GJ, et al. Alpinumisoflavone exhibits the therapeutic effect on prostate cancer cells by repressing AR and co-targeting FASN- and HMGCR-mediated lipid and cholesterol biosynthesis. Life. 2022;12:1769.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Damiano F, Giannotti L, Gnoni GV, Siculella L, Gnoni A. Quercetin inhibition of SREBPs and ChREBP expression results in reduced cholesterol and fatty acid synthesis in C6 glioma cells. Int J Biochem Cell Biol. 2019;117:105618.

    Article  CAS  PubMed  Google Scholar 

  31. Feltrin S, Ravera F, Traversone N, Ferrando L, Bedognetti D, Ballestrero A, et al. Sterol synthesis pathway inhibition as a target for cancer treatment. Cancer Lett. 2020;493:19–30.

    Article  CAS  PubMed  Google Scholar 

  32. Liu D, Wong CC, Fu L, Chen H, Zhao L, Li C, et al. Squalene epoxidase drives NAFLD-induced hepatocellular carcinoma and is a pharmaceutical target. Sci Transl Med. 2018;10:eaap9840.

    Article  PubMed  Google Scholar 

  33. Li C, Wang Y, Liu D, Wong CC, Coker OO, Zhang X, et al. Squalene epoxidase drives cancer cell proliferation and promotes gut dysbiosis to accelerate colorectal carcinogenesis. Gut. 2022;71:2253–65.

    Article  CAS  PubMed  Google Scholar 

  34. He L, Li H, Pan C, Hua Y, Peng J, Zhou Z, et al. Squalene epoxidase promotes colorectal cancer cell proliferation through accumulating calcitriol and activating CYP24A1-mediated MAPK signaling. Cancer Commun. 2021;41:726–46.

    Article  Google Scholar 

  35. Jun SY, Brown AJ, Chua NK, Yoon JY, Lee JJ, Yang JO, et al. Reduction of squalene epoxidase by cholesterol accumulation accelerates colorectal cancer progression and metastasis. Gastroenterology. 2021;160:1194–1207.e28.

    Article  CAS  PubMed  Google Scholar 

  36. Dai M, Zhu XL, Liu F, Xu QY, Ge QL, Jiang SH, et al. Cholesterol synthetase DHCR24 induced by insulin aggravates cancer invasion and progesterone resistance in endometrial carcinoma. Sci Rep. 2017;7:41404.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Qiu T, Cao J, Chen W, Wang J, Wang Y, Zhao L, et al. 24-Dehydrocholesterol reductase promotes the growth of breast cancer stem-like cells through the Hedgehog pathway. Cancer Sci. 2020;111:3653–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Shen Y, Zhou J, Nie K, Cheng S, Chen Z, Wang W, et al. Oncogenic role of the SOX9-DHCR24-cholesterol biosynthesis axis in IGH-BCL2+ diffuse large B-cell lymphomas. Blood. 2022;139:73–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Wu J, Guo L, Qiu X, Ren Y, Li F, Cui W, et al. Genkwadaphnin inhibits growth and invasion in hepatocellular carcinoma by blocking DHCR24-mediated cholesterol biosynthesis and lipid rafts formation. Br J Cancer. 2020;123:1673–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Zhang R, Zeng J, Liu W, Meng J, Wang C, Shi L, et al. The role of NPC1L1 in cancer. Front Pharmacol. 2022;13:956619.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Zhang R, Liu W, Zeng J, Meng J, Jiang H, Wang J, et al. Niemann-pick C1-like 1 inhibitors for reducing cholesterol absorption. Eur J Med Chem. 2022;230:114111.

    Article  CAS  PubMed  Google Scholar 

  42. Zhang Z, Qin S, Chen Y, Zhou L, Yang M, Tang Y, et al. Inhibition of NPC1L1 disrupts adaptive responses of drug-tolerant persister cells to chemotherapy. EMBO Mol Med. 2022;14:e14903.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Tomeh MA, Hadianamrei R, Zhao X. A review of curcumin and its derivatives as anticancer agents. Int J Mol Sci. 2019;20:1033.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Qin S, Su Q, Li X, Shao M, Zhang Y, Yu F, et al. Curcumin suppresses cell proliferation and reduces cholesterol absorption in Caco-2 cells by activating the TRPA1 channel. Lipids Health Dis. 2023;22:6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Zeng J, Liu W, Liang B, Shi L, Yang S, Meng J, et al. Inhibitory effect of isoliquiritigenin in Niemann-pick C1-like 1-mediated cholesterol uptake. Molecules. 2022;27:7494.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Liu W, Liang B, Zeng J, Meng J, Shi L, Yang S, et al. First discovery of cholesterol-lowering activity of parthenolide as NPC1L1 inhibitor. Molecules. 2022;27:6270.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Chen Z, Chen L, Sun B, Liu D, He Y, Qi L, et al. LDLR inhibition promotes hepatocellular carcinoma proliferation and metastasis by elevating intracellular cholesterol synthesis through the MEK/ERK signaling pathway. Mol Metab. 2021;51:101230.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Lee SJ, Choi YJ, Kim HI, Moon HE, Paek SH, Kim TY, et al. Platycodin D inhibits autophagy and increases glioblastoma cell death via LDLR upregulation. Mol Oncol. 2022;16:250–68.

    Article  CAS  PubMed  Google Scholar 

  49. Young SG. Recent progress in understanding apolipoprotein B. Circulation. 1990;82:1574–94.

    Article  CAS  PubMed  Google Scholar 

  50. Borradaile NM, de Dreu LE, Wilcox LJ, Edwards JY, Huff MW. Soya phytoestrogens, genistein and daidzein, decrease apolipoprotein B secretion from HepG2 cells through multiple mechanisms. Biochem J. 2002;366:531–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Yuan J, Cai T, Zheng X, Ren Y, Qi J, Lu X, et al. Potentiating CD8+ T cell antitumor activity by inhibiting PCSK9 to promote LDLR-mediated TCR recycling and signaling. Protein Cell. 2021;12:240–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Bergeron N, Phan BA, Ding Y, Fong A, Krauss RM. Proprotein convertase subtilisin/kexin type 9 inhibition: a new therapeutic mechanism for reducing cardiovascular disease risk. Circulation. 2015;132:1648–66.

    Article  CAS  PubMed  Google Scholar 

  53. Lagace TA, Curtis DE, Garuti R, McNutt MC, Park SW, Prather HB, et al. Secreted PCSK9 decreases the number of LDL receptors in hepatocytes and in livers of parabiotic mice. J Clin Invest. 2006;116:2995–3005.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Yang QC, Wang S, Liu YT, Song A, Wu ZZ, Wan SC, et al. Targeting PCSK9 reduces cancer cell stemness and enhances antitumor immunity in head and neck cancer. iScience. 2023;26:106916.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Abdelwahed KS, Siddique AB, Qusa MH, King JA, Souid S, Abd Elmageed ZY, et al. PCSK9 axis-targeting Pseurotin A as a novel prostate cancer recurrence suppressor lead. ACS Pharmacol Transl Sci. 2021;4:1771–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Abdelwahed KS, Siddique AB, Mohyeldin MM, Qusa MH, Goda AA, Singh SS, et al. Pseurotin A as a novel suppressor of hormone dependent breast cancer progression and recurrence by inhibiting PCSK9 secretion and interaction with LDL receptor. Pharmacol Res. 2020;158:104847.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Chen HC, Chen PY, Wu MJ, Tai MH, Yen JH. Tanshinone IIA modulates low density lipoprotein uptake via down-regulation of PCSK9 gene expression in HepG2 cells. PLoS One. 2016;11:e0162414.

    Article  PubMed  PubMed Central  Google Scholar 

  58. Shen WJ, Azhar S, Kraemer FB. SR-B1: A unique multifunctional receptor for cholesterol influx and efflux. Annu Rev Physiol. 2018;80:95–116.

    Article  CAS  PubMed  Google Scholar 

  59. Schörghofer D, Kinslechner K, Preitschopf A, Schütz B, Röhrl C, Hengstschläger M, et al. The HDL receptor SR-BI is associated with human prostate cancer progression and plays a possible role in establishing androgen independence. Reprod Biol Endocrinol. 2015;13:88.

    Article  PubMed  PubMed Central  Google Scholar 

  60. Gordon JA, Noble JW, Midha A, Derakhshan F, Wang G, Adomat HH, et al. Upregulation of scavenger receptor B1 is required for steroidogenic and nonsteroidogenic cholesterol metabolism in prostate cancer. Cancer Res. 2019;79:3320–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Zheng Y, Liu Y, Jin H, Pan S, Qian Y, Huang C, et al. Scavenger receptor B1 is a potential biomarker of human nasopharyngeal carcinoma and its growth is inhibited by HDL-mimetic nanoparticles. Theranostics. 2013;3:477–86.

    Article  PubMed  PubMed Central  Google Scholar 

  62. Smith RC, Bulanadi JC, Gill AJ, Rye KA, Hugh T, Proschogo N, et al. Pancreatic adenocarcinoma preferentially takes up and is suppressed by synthetic nanoparticles carrying apolipoprotein A-II and a lipid gemcitabine prodrug in mice. Cancer Lett. 2020;495:112–22.

    Article  CAS  PubMed  Google Scholar 

  63. Chen Q, Wang L, Song H, Xing W, Shi J, Li Y, et al. Deficiency of SR-B1 reduced the tumor load of colitis-induced or APCmin/+ -induced colorectal cancer. Cancer Med. 2023;12:19744–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Lee BH, Taylor MG, Robinet P, Smith JD, Schweitzer J, Sehayek E, et al. Dysregulation of cholesterol homeostasis in human prostate cancer through loss of ABCA1. Cancer Res. 2013;73:1211–8.

    Article  CAS  PubMed  Google Scholar 

  65. Sekine Y, Demosky SJ, Stonik JA, Furuya Y, Koike H, Suzuki K, et al. High-density lipoprotein induces proliferation and migration of human prostate androgen-independent cancer cells by an ABCA1-dependent mechanism. Mol Cancer Res. 2010;8:1284–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Zhang CJ, Zhu N, Long J, Wu HT, Wang YX, Liu BY, et al. Celastrol induces lipophagy via the LXRα/ABCA1 pathway in clear cell renal cell carcinoma. Acta Pharmacol Sin. 2021;42:1472–85.

    Article  CAS  PubMed  Google Scholar 

  67. Sharma B, Agnihotri N. Role of cholesterol homeostasis and its efflux pathways in cancer progression. J Steroid Biochem Mol Biol. 2019;191:105377.

    Article  CAS  PubMed  Google Scholar 

  68. Gelissen IC, Harris M, Rye KA, Quinn C, Brown AJ, Kockx M, et al. ABCA1 and ABCG1 synergize to mediate cholesterol export to apoA-I. Arterioscler Thromb Vasc Biol. 2006;26:534–40.

    Article  CAS  PubMed  Google Scholar 

  69. Sag D, Cekic C, Wu R, Linden J, Hedrick CC. The cholesterol transporter ABCG1 links cholesterol homeostasis and tumour immunity. Nat Commun. 2015;6:6354.

    Article  CAS  PubMed  Google Scholar 

  70. Hoppstädter J, Dembek A, Höring M, Schymik HS, Dahlem C, Sultan A, et al. Dysregulation of cholesterol homeostasis in human lung cancer tissue and tumour-associated macrophages. EBioMedicine. 2021;72:103578.

    Article  PubMed  PubMed Central  Google Scholar 

  71. Huang C. Natural modulators of liver X receptors. J Integr Med. 2014;12:76–85.

    Article  PubMed  Google Scholar 

  72. Elia J, Carbonnelle D, Logé C, Ory L, Huvelin JM, Tannoury M, et al. 4-cholesten-3-one decreases breast cancer cell viability and alters membrane raft-localized EGFR expression by reducing lipogenesis and enhancing LXR-dependent cholesterol transporters. Lipids Health Dis. 2019;18:168.

    Article  PubMed  PubMed Central  Google Scholar 

  73. Ceroi A, Masson D, Roggy A, Roumier C, Chagué C, Gauthier T, et al. LXR agonist treatment of blastic plasmacytoid dendritic cell neoplasm restores cholesterol efflux and triggers apoptosis. Blood. 2016;128:2694–707.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Moschetta A. Nuclear receptor LXR as a novel therapeutic antitumoral target in glioblastoma. Cancer Discov. 2011;1:381–2.

    Article  CAS  PubMed  Google Scholar 

  75. Wu G, Wang Q, Xu Y, Li J, Zhang H, Qi G, et al. Targeting the transcription factor receptor LXR to treat clear cell renal cell carcinoma: agonist or inverse agonist? Cell Death Dis. 2019;10:416.

    Article  PubMed  PubMed Central  Google Scholar 

  76. Pattanayak SP, Bose P, Sunita P, Siddique MUM, Lapenna A. Bergapten inhibits liver carcinogenesis by modulating LXR/PI3K/Akt and IDOL/LDLR pathways. Biomed Pharmacother. 2018;108:297–308.

    Article  CAS  PubMed  Google Scholar 

  77. Guo D, Reinitz F, Youssef M, Hong C, Nathanson D, Akhavan D, et al. An LXR agonist promotes glioblastoma cell death through inhibition of an EGFR/AKT/SREBP-1/LDLR-dependent pathway. Cancer Discov. 2011;1:442–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Resetar M, Tietcheu Galani BR, Tsamo AT, Chen Y, Schachner D, Stolzlechner S, et al. Flindissone, a limonoid isolated from trichilia prieuriana, is an LXR agonist. J Nat Prod. 2023;86:1901–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Yang CM, Lu YL, Chen HY, Hu ML. Lycopene and the LXRα agonist T0901317 synergistically inhibit the proliferation of androgen-independent prostate cancer cells via the PPARγ-LXRα-ABCA1 pathway. J Nutr Biochem. 2012;23:1155–62.

    Article  CAS  PubMed  Google Scholar 

  80. Chang TY, Chang CC, Ohgami N, Yamauchi Y. Cholesterol sensing, trafficking, and esterification. Annu Rev Cell Dev Biol. 2006;22:129–57.

    Article  CAS  PubMed  Google Scholar 

  81. Geng F, Cheng X, Wu X, Yoo JY, Cheng C, Guo JY, et al. Inhibition of SOAT1 suppresses glioblastoma growth via blocking SREBP-1-mediated lipogenesis. Clin Cancer Res. 2016;22:5337–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Li J, Gu D, Lee SS, Song B, Bandyopadhyay S, Chen S, et al. Abrogating cholesterol esterification suppresses growth and metastasis of pancreatic cancer. Oncogene. 2016;35:6378–88.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Ye K, Wu Y, Sun Y, Lin J, Xu J. TLR4 siRNA inhibits proliferation and invasion in colorectal cancer cells by downregulating ACAT1 expression. Life Sci. 2016;155:133–9.

    Article  CAS  PubMed  Google Scholar 

  84. Yue S, Li J, Lee SY, Lee HJ, Shao T, Song B, et al. Cholesteryl ester accumulation induced by PTEN loss and PI3K/AKT activation underlies human prostate cancer aggressiveness. Cell Metab. 2014;19:393–406.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Long T, Sun Y, Hassan A, Qi X, Li X. Structure of nevanimibe-bound tetrameric human ACAT1. Nature. 2020;581:339–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Zhu Y, Gu L, Lin X, Zhou X, Lu B, Liu C, et al. P53 deficiency affects cholesterol esterification to exacerbate hepatocarcinogenesis. Hepatology. 2023;77:1499–511.

    Article  PubMed  Google Scholar 

  87. Yang W, Bai Y, Xiong Y, Zhang J, Chen S, Zheng X, et al. Potentiating the antitumour response of CD8+ T cells by modulating cholesterol metabolism. Nature. 2016;531:651–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Lee HJ, Li J, Vickman RE, Li J, Liu R, Durkes AC, et al. Cholesterol esterification inhibition suppresses prostate cancer metastasis by impairing the Wnt/β-catenin pathway. Mol Cancer Res. 2018;16:974–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Ohmoto T, Nishitsuji K, Yoshitani N, Mizuguchi M, Yanagisawa Y, Saito H, et al. K604, a specific acyl‑CoA:cholesterol acyltransferase 1 inhibitor, suppresses proliferation of U251‑MG glioblastoma cells. Mol Med Rep. 2015;12:6037–42.

    Article  CAS  PubMed  Google Scholar 

  90. Shim SH, Sur S, Steele R, Albert CJ, Huang C, Ford DA, et al. Disrupting cholesterol esterification by bitter melon suppresses triple-negative breast cancer cell growth. Mol Carcinog. 2018;57:1599–607.

    Article  CAS  PubMed  Google Scholar 

  91. Lin LC, Chang HY, Kuo TT, Chen HY, Liu WS, Lo YJ, et al. Oxidative stress mediates the inhibitory effects of Manzamine A on uterine leiomyoma cell proliferation and extracellular matrix deposition via SOAT inhibition. Redox Biol. 2023;66:102861.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Wilcox LJ, Borradaile NM, de Dreu LE, Huff MW. Secretion of hepatocyte apoB is inhibited by the flavonoids, naringenin and hesperetin, via reduced activity and expression of ACAT2 and MTP. J Lipid Res. 2001;42:725–34.

    Article  CAS  PubMed  Google Scholar 

  93. Li Y, Ran Q, Duan Q, Jin J, Wang Y, Yu L, et al. 7-Dehydrocholesterol dictates ferroptosis sensitivity. Nature. 2024;626:411–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Li Q, Chan H, Liu WX, Liu CA, Zhou Y, Huang D, et al. Carnobacterium maltaromaticum boosts intestinal vitamin D production to suppress colorectal cancer in female mice. Cancer Cell. 2023;41:1450–1465.e8.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by the National Natural Science Foundation of China (82274153, 82322073, and 82173846), Youth Project of Shanghai Oriental Talents Program (QNWS2024102), Oriental Scholars of Shanghai University (TP2022081), Shuguang Program of Shanghai Education Commission, Youth Project of Shanghai Oriental Talents Program, Jiangxi Province Thousand Talents Program (jxsq2023102168), Young Talent Lifting Project of China Association of Chinese Medicine [NCACM-(2021-QNRC2-A08)], Shanghai Rising-Star Program (22QA1409100), High-level Key Discipline of National Administration of Traditional Chinese Medicine (zyyzdxk-2023071), Three-year Action Plan for Shanghai TCM Development and Inheritance Program (2-2-1), Innovation Team of High-level Local Universities in Shanghai: Strategic Innovation Team of TCM Chemical Biology, CAMS Innovation Fund for Medical Sciences (CIFMS, 2023-I2M-3-009), the Organizational Key Research and Development Program of Shanghai University of Traditional Chinese Medicine (2023YZZ02), Open Project of Guangxi Key Laboratory of Bioactive Molecules Research and Evaluation (BMRE2024-KF04), National Key Laboratory of Lead Druggability Research (NKLYT2023010), and China Postdoctoral Science Foundation (2024M762110).

Author information

Authors and Affiliations

  1. Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research and Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China

    Chun-lan Dai, Zi-yang Qiu, An-qi Wang, Shen Yan, Li-jun Zhang & Xin Luan

Authors
  1. Chun-lan Dai
    View author publications

    Search author on:PubMed Google Scholar

  2. Zi-yang Qiu
    View author publications

    Search author on:PubMed Google Scholar

  3. An-qi Wang
    View author publications

    Search author on:PubMed Google Scholar

  4. Shen Yan
    View author publications

    Search author on:PubMed Google Scholar

  5. Li-jun Zhang
    View author publications

    Search author on:PubMed Google Scholar

  6. Xin Luan
    View author publications

    Search author on:PubMed Google Scholar

Corresponding authors

Correspondence to Li-jun Zhang or Xin Luan.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Dai, Cl., Qiu, Zy., Wang, Aq. et al. Targeting cholesterol metabolism: a promising therapy strategy for cancer. Acta Pharmacol Sin 46, 2093–2104 (2025). https://doi.org/10.1038/s41401-025-01531-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Version of record:

  • Issue date:

  • DOI: https://doi.org/10.1038/s41401-025-01531-9

Keywords

This article is cited by

Search

Advanced search

Quick links