Tumor peripheral stiffness modulates lenvatinib resistance in HCC preclinical models by regulating FIS1-dependent mitophagy

Background & Aims: Hepatocellular carcinoma (HCC) displays heterogeneous responses to lenvatinib, with tumor microenvironment (TME) stiffness emerging as a key resistance modulator. This study investigates how tumor peripheral stiffness governs lenvatinib efficacy via mitochondrial fission/mitophagy and evaluates matrix-targeting combination therapies. Methods: 15 kPa) were assessed for their lenvatinib response, mitophagy, and mitochondrial fission 1 (FIS1)-trimethylation of histone H3 lysine 27 (H3K27me3) regulation. Subcutaneous xenografts received collagenase-lenvatinib combination therapy. Results: <0.001) while reducing FIS1/Parkin expression and augmenting apoptosis. Conclusions: Tumor peripheral stiffness drives lenvatinib resistance in HCC via H3K27me3-mediated FIS1 upregulation, triggering mitochondrial fission and cytoprotective mitophagy to evade drug-induced apoptosis. Targeting matrix stiffness (via collagenase-mediated softening) synergizes with lenvatinib to overcome microenvironment-driven resistance, providing a novel mechanoadjuvant strategy for HCC therapy. Impact and implications: imaging/biopsy) could be used to stratify patients for personalized treatment. Combining lenvatinib with matrix-softening agents or mitophagy inhibitors could improve efficacy. However, translational potential requires validation in larger cohorts and development of non-invasive stiffness measurement methods, given challenges associated with the clinical application of current invasive techniques or collagenase-based preclinical models.