Evidence map›Paper›PMID 41559318›Full record

ArticleEuropean 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 Surgery2026

Therapeutic targeting of the FSP1-ACSL4 axis reverses cisplatin resistance via ferroptosis induction in drug-tolerant papillary thyroid carcinoma.

Chien-Yi Yang, Chih-Ming Huang, Muhammad Yasir, Chun-Chen Ko, Vijesh Kumar Yadav, Shao-Cheng Liu

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Article in 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. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

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5 · Who and what money

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6 authors.

Chien-Yi YangDivision of General Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical University, Taipei, Taiwan, Republic of China.
Chih-Ming HuangDepartment of Otolaryngology, Taitung Mackay Memorial Hospital, Taitung City, 950408, Taiwan.
Muhammad YasirDivision of Hematology and Oncology, Taipei Medical University Shuang Ho Hospital, New Taipei City, 23561, Taiwan.
Chun-Chen KoDivision of Hematology and Oncology, Taipei Medical University Shuang Ho Hospital, New Taipei City, 23561, Taiwan.
Vijesh Kumar YadavDivision of Hematology and Oncology, Taipei Medical University Shuang Ho Hospital, New Taipei City, 23561, Taiwan.
Shao-Cheng LiuDepartment of Otolaryngology-Head and Neck Surgery, Tri-Service General Hospital, National Defense Medical University, No. 325, Sec. 2, Cheng-Gong Road, Neihu District, Taipei, 114, Taiwan, Republic of China. m871435@ndmctsgh.edu.tw.ORCID http://orcid.org/0000-0001-9730-1798

Funding

National Science and Technology Council NSTC 113-2314-B-016-007
6 · The paper itself

Abstract

backgroundCisplatin 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.

methodsCisplatin-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.

resultsResistant 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.

conclusionFSP1 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.

Indexed as

Antineoplastic AgentsCisplatinCoenzyme A LigasesDrug Resistance, NeoplasmFerroptosisS100 Calcium-Binding Protein A4Thyroid Cancer, PapillaryThyroid NeoplasmsCell Line, TumorHumansLong-Chain-Fatty-Acid-CoA LigaseAntineoplastic AgentsCisplatinCoenzyme A LigasesLong-Chain-Fatty-Acid-CoA LigaseS100A4 protein, humanS100 Calcium-Binding Protein A4Drug resistanceDrug-Tolerant persistent cellsFerroptosisFSP1Papillary thyroid carcinoma (PTC)

Identifiers

PMID41559318

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