Scholarlink

Background <p>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.</p> Methods <p>Cisplatin-resistant PTC tissues and primary DTP cells from recurrent cases were examined alongside in-vitro DTP models (8505&#xa0;C and K1). FSP1 and ferroptosis markers were profiled by qPCR, immunofluorescence, and RNA-seq.&#xa0;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.</p> Results <p>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 (<i>p</i> &lt; 0.001). In contrast, ACSL4 targeting conferred no additional benefit.</p> Conclusion <p>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.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

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

  • 期刊论文

  • 发表日期：

    2026年1月20日

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

摘要

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.