Lung cancer is the leading cause of cancer-related death worldwide, with over 1 million new cases diagnosed each year [1]. Lung cancer is classified into two types: small-cell lung cancer and non-small cell lung cancer (NSCLC), with the latter accounting for around 85% of all cases [2]. Despite decades of advancements in NSCLC treatment, patient survival remains unsatisfied. Thus, novel effective treatment strategies are urgently required.

Ferroptosis is a programmed cell death that depends on iron and differs from apoptosis, necroptosis, and autophagy [3]. Iron metabolism dysregulation, antioxidant imbalance, and lipid peroxide accumulation cause ferroptosis [4]. Cellular iron levels must be maintained to prevent the Fenton reaction from generating reactive oxygen species (ROS) [5]. Iron is necessary for several physiological functions. Iron homeostasis involves several proteins. The transferrin receptor 1 (TFR1) transmembrane glycoprotein internalizes transferrin-bound iron [6]. In cells, ferritins store non-toxic iron in the cytoplasm [6]. Two subunits—a heavy subunit (FTH) and a light subunit (FTL)—make up ferritin [6]. Ferroptosis is regulated by glutathione peroxidase 4 (GPX4) [7]. Reduced glutathione helps GPX4 convert lipid hydroperoxides into lipid alcohols, preventing lipid peroxidation and ferroptosis [7]. The Kelch-like ECH-associated protein 1 (Keap1) proteasomally degrades the transcription factor nuclear factor (erythroid-derived 2)-like 2 (Nrf2), which regulates GPX4 levels [8]. Targeting ferroptosis may kill apoptosis-resistant cancer cells.

Due to their effectiveness and safety, natural products have garnered attention in cancer treatment. Many natural products can induce ferroptosis in cancer cells. Icariside II induces ferroptosis in renal cell carcinoma cells [9]. In leukemia cells, sulforaphane induces ferroptosis [10]. Trabectedin, also known as Yondelis or Ecteinascidin-743, is an anti-cancer drug isolated from the marine organism Ecteinascidia turbinate [11]. Trabectedin is approved for treating soft tissue sarcoma and ovarian cancer [12,13]. Trabectedin also inhibits breast cancer [14]. However, trabectedin's effects on NSCLC remain unknown.

This study aimed to investigate Trabectedin's anti-NSCLC effects. Our results showed that trabectedin could induce ferroptosis in NSCLC cells. Trabectedin regulates the HIF-1α/IRP1/TFR1 and Keap1/Nrf2/GPX4 axes in NSCLC cells. Our findings suggest that Trabectedin may be used to treat NSCLC.