Abstract
Non-small-cell lung cancer (NSCLC) ranks among the most prevalent causes of cancer-related mortality worldwide, with cisplatin-based chemotherapy being a cornerstone of clinical treatment despite the inevitable emergence of drug resistance. This study systematically investigated the molecular mechanisms underlying cisplatin resistance in NSCLC, focusing on the role of TWF1 in regulating ferroptosis. Mechanistic analyses revealed that TWF1 acts as a dual-function suppressor of ferroptosis. Through direct interaction with p53, TWF1 inhibits p53 nuclear translocation, thereby upregulating SLC7A11 and promoting system Xc⁻-mediated cystine uptake, which supports GSH biosynthesis and redox homeostasis. TWF1 induces autophagy-related metabolic reprogramming, increasing intracellular glutamate levels to sustain system Xc⁻ activity and suppress lipid peroxidation. In cisplatin-resistant A549/cisplatin (DDP) cells, TWF1 knockdown significantly reduced SLC7A11 expression, depleted GSH reserves, and enhanced lipid reactive oxygen species (ROS) accumulation, sensitizing cells to cisplatin via ferroptosis induction. This study identifies TWF1 as a critical regulator of cisplatin resistance and ferroptosis, highlighting the therapeutic potential of TWF1 inhibition combined with cisplatin to overcome chemoresistance, possibly providing new strategies for improving NSCLC treatment outcomes.