Nanomagnetic Hyperthermia Sensitizes Gemcitabine Chemosensitivity in Pancreatic Cancer by Inhibiting HSPB1 to Amplify ACSL4-Mediated Ferroptosis

Pancreatic cancer, one of the most malignant solid tumors with the poorest prognosis, is commonly treated with gemcitabine (GEM)-based systemic chemotherapy. However, chemoresistance remains a significant therapeutic challenge. Ferroptosis, a novel form of programmed cell death, has demonstrated exceptional susceptibility in chemoresistant cancer cells. Due to their unique magnetic responsiveness, iron oxide nanoparticles can generate heat under alternating magnetic fields, which enables magnetic hyperthermia (MH) therapy. This approach not only directly induces tumor cell apoptosis but also enhances chemosensitization. In this study, we demonstrate that ferrimagnetic vortex-domain iron oxide nanorings (FVIOs) as an ideal nanoplatform for MH, significantly improving GEM chemosensitivity in pancreatic cancer. Both in vitro and in vivo experiments demonstrated that MH not only synergizes with GEM to exhibit an antitumor effect in wild-type (WT) pancreatic tumors, but also directly suppresses the proliferation of gemcitabine-resistant (GR) counterparts while alleviating chemoresistance. High-throughput transcriptomic profiling revealed an increased susceptibility of GR cells to ferroptosis induction. Mechanistically, MH suppressed HSPB1 expression in GR cells, thereby attenuating its regulatory role in the ubiquitination-mediated degradation of ACSL4 protein and ultimately promoting ferroptosis. Comprehensive in vivo evaluations confirmed the multidimensional chemosensitizing efficacy of MH alongside favorable biosafety. Our findings highlight MH as a promising adjuvant strategy for pancreatic cancer, particularly in GEM-resistant cases, by overcoming chemoresistance through the potentiation of ferroptosis.