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

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.