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Peer-reviewedCC BY-NC-ND 4.0Bioactive Materials

Disrupting the cholesterol–mechanics axis enables ferroptosis and deep drug delivery in hepatocellular carcinoma

  • Jinying Zhu1,2
  • Yangping Zhong1
  • Shuangqian Yan2
  • Xuemei Zeng1
  1. 1Key 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, China
  2. 2Strait 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
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Abstract

Hepatocellular carcinoma (HCC) develops within a fibrotic and stiffened microenvironment that limits drug penetration and suppresses regulated cell death, contributing to therapeutic resistance. Here we identify cholesterol as a central regulator linking extracellular matrix (ECM) mechanics to ferroptosis resistance through lipid raft‒mediated mechanotransduction. Spatial transcriptomics of human HCC specimens reveals enrichment of PTK2 (focal adhesion kinase, FAK) and cholesterol-associated pathways at tumor–stroma interfaces, implicating a cholesterol–mechanics axis in tumor progression. To target this vulnerability, we engineer a one-dimensional Fe-Mn oxyhydroxide nanozyme integrated with cholesterol oxidase (FeMnOOH/C). This platform simultaneously depletes cholesterol, disrupts lipid raft signaling, and remodels ECM stiffness, while amplifying ferroptosis through multienzymatic redox catalysis. FeMnOOH/C enhances membrane fluidity, promotes deep tumor penetration, and enables efficient intratumoral delivery of therapeutics. In vivo, FeMnOOH/C induces robust ferroptosis and immunogenic cell death, leading to increased cytotoxic T cell infiltration and marked tumor suppression. These findings establish mechano-metabolic reprogramming (mechanical regulation and cholesterol deprivation) as a strategy to overcome ferroptosis resistance and provide proof-of-concept support for a strategy of targeting fibrotic tumors.

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Cite

BibTeXRIS
BibTeX
@article{zhu2026disrupting,
  title = {{Disrupting the cholesterol–mechanics axis enables ferroptosis and deep drug delivery in hepatocellular carcinoma}},
  author = {Jinying Zhu and Yangping Zhong and Shuangqian Yan and Xuemei Zeng},
  journal = {Bioactive Materials},
  year = {2026},
  month = oct,
  doi = {10.1016/j.bioactmat.2026.09.025},
  url = {https://doi.org/10.1016/j.bioactmat.2026.09.025},
  note = {CC BY-NC-ND 4.0},
}
RIS
TY  - JOUR
TI  - Disrupting the cholesterol–mechanics axis enables ferroptosis and deep drug delivery in hepatocellular carcinoma
AU  - Jinying Zhu
AU  - Yangping Zhong
AU  - Shuangqian Yan
AU  - Xuemei Zeng
PY  - 2026
DA  - 2026/10/27
JO  - Bioactive Materials
DO  - 10.1016/j.bioactmat.2026.09.025
UR  - https://doi.org/10.1016/j.bioactmat.2026.09.025
AB  - Hepatocellular carcinoma (HCC) develops within a fibrotic and stiffened microenvironment that limits drug penetration and suppresses regulated cell death, contributing to therapeutic resistance. Here we identify cholesterol as a central regulator linking extracellular matrix (ECM) mechanics to ferroptosis resistance through lipid raft‒mediated mechanotransduction. Spatial transcriptomics of human HCC specimens reveals enrichment of PTK2 (focal adhesion kinase, FAK) and cholesterol-associated pathways at tumor–stroma interfaces, implicating a cholesterol–mechanics axis in tumor progression. To target this vulnerability, we engineer a one-dimensional Fe-Mn oxyhydroxide nanozyme integrated with cholesterol oxidase (FeMnOOH/C). This platform simultaneously depletes cholesterol, disrupts lipid raft signaling, and remodels ECM stiffness, while amplifying ferroptosis through multienzymatic redox catalysis. FeMnOOH/C enhances membrane fluidity, promotes deep tumor penetration, and enables efficient intratumoral delivery of therapeutics. In vivo, FeMnOOH/C induces robust ferroptosis and immunogenic cell death, leading to increased cytotoxic T cell infiltration and marked tumor suppression. These findings establish mechano-metabolic reprogramming (mechanical regulation and cholesterol deprivation) as a strategy to overcome ferroptosis resistance and provide proof-of-concept support for a strategy of targeting fibrotic tumors.
SN  - 2452-199X
ER  -