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  3. Targeting cancer stem-like cells via cholesterol modulation and ferroptosis induction using a multifunctional nanoplatform to overcome drug resistance

Targeting cancer stem-like cells via cholesterol modulation and ferroptosis induction using a multifunctional nanoplatform to overcome drug resistance

  • J Nanobiotechnology. 2025 Nov 19;23(1):722. doi: 10.1186/s12951-025-03796-y.
Leiguang Ye # 1,  Jinying Zhu # 2,  Xiaoman Wang # 3,  Nianhan Chen 2,  Ying Sun 4,  Xuemei Zeng 5,  Shijian Liu 6 7,  Shuangqian Yan 8
Affiliations

Affiliations

  • 1 Department of Medical Oncology, Affiliated Tumor Hospital of Harbin Medical University, Harbin, PR China.
  • 2 Key Laboratory of Microbial Pathogenesis and Interventions of Fujian Province University, Biomedical Research Center of South China, College of Life Sciences, Fujian Normal University, 1 Keji Road, Fuzhou, 350117, PR China.
  • 3 Strait Institute of Flexible Electronics (SIFE, Future Technologies), Fujian Key Laboratory of Flexible Electronics, Fujian Normal University and Strait Laboratory of Flexible Electronics (SLoFE), Fuzhou, 350117, China.
  • 4 Department of gastroenterology, Fuzhou No. 1 Hospital Affiliated with Fujian Medical University, Fuzhou, China. [email protected].
  • 5 Key Laboratory of Microbial Pathogenesis and Interventions of Fujian Province University, Biomedical Research Center of South China, College of Life Sciences, Fujian Normal University, 1 Keji Road, Fuzhou, 350117, PR China. [email protected].
  • 6 Department of Oncology, Harbin Medical University Cancer Hospital, Harbin, China. [email protected].
  • 7 Department of Nephrology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China. [email protected].
  • 8 Strait Institute of Flexible Electronics (SIFE, Future Technologies), Fujian Key Laboratory of Flexible Electronics, Fujian Normal University and Strait Laboratory of Flexible Electronics (SLoFE), Fuzhou, 350117, China. [email protected].
  • # Contributed equally.
PMID: 41261412 DOI: 10.1186/s12951-025-03796-y
Abstract

Overcoming therapy resistance in triple-negative breast Cancer (TNBC) requires the effective targeting of Cancer stem-like cells (CSCs). TNBC is characterized by hyperactivation of the mevalonate pathway, leading to Cholesterol accumulation in CSC membranes, which alters membrane properties, enhances stemness, and restricts both drug penetration and lipid peroxidation-a key driver of Ferroptosis. Here, we develop Fe/CDP, a nanoparticle with a Fe3O4 core coated with chondroitin sulfate and loaded with pravastatin, a mevalonate pathway inhibitor, and doxorubicin (DOX). In TNBC mouse models, Fe/CDP selectively targets tumors and CSCs via CD44-chondroitin sulfate interactions, enabling localized drug release. Pravastatin suppresses Cholesterol biosynthesis, restoring membrane rigidity and fluidity, thereby reducing CSC stemness, disrupting P-glycoprotein function, and downregulating ALDH1, which enhances DOX sensitivity via the EGFR/Src/HMGCR axis. Moreover, Cholesterol depletion facilitates lipid peroxidation, synergizing with Fe3O4 to trigger Ferroptosis through CoQ10/GPX4/FSP1 downregulation. By eliminating both bulk tumor cells and CSCs, Fe/CDP provides a cholesterol-modulating strategy to overcome TNBC drug resistance.

Keywords

Cancer stem cell; Cholesterol depletion; Drug resistance; MVA pathway; Membrane modulation.

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