HELLS inhibits autophagy‑dependent ferroptosis in nasopharyngeal carcinoma by modulating the Nrf2/HO‑1/GPX4 pathway

The present study aimed to elucidate the role of lymphoid‑specific helicase (HELLS) in autophagy‑dependent ferroptosis in nasopharyngeal carcinoma (NPC) cells and associated mechanisms. Bioinformatics analyses were conducted to identify the key gene. Gene knockout was accomplished through short‑hairpin RNA transfection. Reverse transcription‑quantitative polymerase chain reaction was conducted to evaluate mRNA expression, whereas protein expression was assessed through immunohistochemistry and western blotting. Furthermore, cell proliferation, migration, invasion and apoptosis were investigated via the Cell Counting Kit‑8, Transwell and flow cytometry assays. Glutathione (GSH), malondialdehyde (MDA) and Fe²⁺ were quantified using commercial reagent kits. Reactive oxygen species (ROS) were assessed through immunofluorescence. Additionally, a tumor xenograft mouse model was employed for <i>in vivo</i> validation. HELLS, upregulated in human NPC tissue, was selected from 15 candidate genes. HELLS knockout resulted in decreased proliferation, migration and invasion while promoting apoptosis and autophagy in NPC/HK1 cells. Furthermore, the administration of ferroptosis and autophagy agonists increased the levels of MDA, Fe²⁺, 4‑hydroxynonenal and ROS, as well as the expression of acyl‑CoA synthetase long‑chain family member 4 and prostaglandin‑endoperoxide synthase 2. Conversely, GSH levels decreased. These observed trends can be reversed by ferroptosis and autophagy inhibitors. HELLS knockout also caused the downregulation of nuclear factor‑erythroid 2‑related factor 2 (Nrf2), heme oxygenase‑1 (HO‑1) and glutathione peroxidase 4 (GPX4), which can be modulated by Nrf2 agonist. In <i>in vivo</i> experiments, HELLS expression reduction inhibited tumor growth and the expression of Nrf2, HO‑1 and GPX4 while promoting autophagy. In conclusion, HELLS activates the Nrf2/HO‑1/GPX4 pathway, which inhibits autophagy‑dependent ferroptosis in NPC cells, thereby promoting NPC progression.