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

作者：Kunjin Wu, Huijuan Li, Yunong Fu, Kaibo Yang, Ting Lin, Yaohui Wang, Ming Wang, Yunxiang Long, Fengping Zhang, Bo Cheng, Yuan Li, Cong Wang, Feng Xu, Chang Liu, Kai Qu · 发表于：JHEP Reports · 年份：2025 · DOI：10.1016/j.jhepr.2025.101588 · 被引用次数：2 · 研究领域：Autophagy in Disease and Therapy、Caveolin-1 and cellular processes、Cancer Research and Treatments

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 i...