European archives of oto-rhino-laryngology : official journal of the European Federation of Oto-Rhino-Laryngological Societies (EUFOS) : affiliated with the German Society for Oto-Rhino-Laryngology - Head and Neck Surgery · 2026
Therapeutic targeting of the FSP1-ACSL4 axis reverses cisplatin resistance via ferroptosis induction in drug-tolerant papillary thyroid carcinoma.
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Yang Chien-Yi, Huang Chih-Ming, Yasir Muhammad, Ko Chun-Chen, Yadav Vijesh Kumar, Liu Shao-Cheng
Аннотация
BACKGROUND: Cisplatin resistance remains a major obstacle in treating recurrent or refractory papillary thyroid carcinoma (PTC). A key driver of this failure is the emergence of drug-tolerant persister (DTP) cells, which enter a reversible quiescent state to evade chemotherapy. Ferroptosis-an iron-dependent, lipid peroxidation-driven form of cell death-has recently gained attention as a strategy to overcome such tolerance. This study investigated the role of ferroptosis suppressor protein-1 (FSP1) and its interplay with acyl-CoA synthetase long-chain family member-4 (ACSL4) in modulating ferroptosis sensitivity and cisplatin resistance in PTC.
METHODS: Cisplatin-resistant PTC tissues and primary DTP cells from recurrent cases were examined alongside in-vitro DTP models (8505 C and K1). FSP1 and ferroptosis markers were profiled by qPCR, immunofluorescence, and RNA-seq. Functional relevance was tested through ACSL4 knockdown (shACSL4) and pharmacologic FSP1 inhibition (iFSP1), alone or combined with cisplatin. Ferroptosis and metabolic states were assessed using viability, GSH/GSSG, lipid ROS, and Seahorse XF assays.
RESULTS: Resistant tumors and DTP cells exhibited marked FSP1 upregulation with concurrent ACSL4 suppression, forming an FSP1-high/ACSL4-low adaptive state dependent on FSP1. iFSP1 treatment alone triggered pronounced ferroptosis, lipid peroxide accumulation, mitochondrial depolarization, and metabolic collapse, sharply restoring cisplatin sensitivity (p < 0.001). In contrast, ACSL4 targeting conferred no additional benefit.
CONCLUSION: FSP1 acts as a metabolic safeguard maintaining ferroptosis resistance and drug tolerance in PTC. Its inhibition disrupts mitochondrial integrity and reinstates ferroptotic vulnerability, positioning FSP1 as a promising therapeutic target to eliminate drug-tolerant persister cells and reverse cisplatin resistance.
METHODS: Cisplatin-resistant PTC tissues and primary DTP cells from recurrent cases were examined alongside in-vitro DTP models (8505 C and K1). FSP1 and ferroptosis markers were profiled by qPCR, immunofluorescence, and RNA-seq. Functional relevance was tested through ACSL4 knockdown (shACSL4) and pharmacologic FSP1 inhibition (iFSP1), alone or combined with cisplatin. Ferroptosis and metabolic states were assessed using viability, GSH/GSSG, lipid ROS, and Seahorse XF assays.
RESULTS: Resistant tumors and DTP cells exhibited marked FSP1 upregulation with concurrent ACSL4 suppression, forming an FSP1-high/ACSL4-low adaptive state dependent on FSP1. iFSP1 treatment alone triggered pronounced ferroptosis, lipid peroxide accumulation, mitochondrial depolarization, and metabolic collapse, sharply restoring cisplatin sensitivity (p < 0.001). In contrast, ACSL4 targeting conferred no additional benefit.
CONCLUSION: FSP1 acts as a metabolic safeguard maintaining ferroptosis resistance and drug tolerance in PTC. Its inhibition disrupts mitochondrial integrity and reinstates ferroptotic vulnerability, positioning FSP1 as a promising therapeutic target to eliminate drug-tolerant persister cells and reverse cisplatin resistance.