A ferroptosis-related lncRNAs risk score model identifies LINC02178 as a potential regulator of ferroptosis sensitivity in cervical cancer

Background Cervical cancer remains a major global health burden among women. Persistent infection with high-risk human papillomavirus (HR-HPV) is the primary driver of cervical carcinogenesis, yet additional cellular regulatory processes are required for tumor progression. Ferroptosis, an iron-dependent form of regulated cell death, has been implicated in cancer metabolism and therapeutic response. However, the involvement of ferroptosis-related long non-coding RNAs (FRLs) in human papillomavirus (HPV)-associated cervical cancer remains insufficiently understood. Methods Transcriptomic and clinical data from The Cancer Genome Atlas (TCGA) and UCSC Xena were analyzed to identify FRLs. A prognostic risk-scoring model (RSM) was constructed using LASSO Cox regression and evaluated by survival analysis and time-dependent receiver operating characteristic (ROC) curves. Expression patterns of selected FRLs were further examined in cervical swab samples with different HPV infection subtypes using quantitative polymerase chain reaction (qPCR). Functional validation was performed in HPV16-positive SiHa cells following small interfering RNA (siRNA)-mediated knockdown of LINC02178, combined with ferroptosis modulation using Erastin or Ferrostatin-1. Cell viability, migration, and ferroptosis-associated biochemical indicators were assessed. Results A prognostic model based on 22 FRLs showed stable predictive performance and remained an independent prognostic factor after adjustment for clinical variables. Among these FRLs, LINC02178 emerged as a standout risk factor, exhibiting markedly elevated expression in HPV16-positive tissues and a strong positive correlation with the lipid droplet-associated protein PLIN2—suggesting a potential role in lipid metabolism. In vitro experiments demonstrated that LINC02178 knockdown inhibited cell proliferation and migration. Furthermore, silencing LINC02178 increased cellular susceptibility to ferroptosis, as reflected by altered redox status and enhanced oxidative stress, particularly under erastin treatment, evidenced by surging levels of reactive oxygen species (ROS), malondialdehyde (MDA), and ferrous iron accumulation (Fe² + ) alongside depleted glutathione (GSH). These findings suggest that LINC02178 potentially serves as a critical metabolic shield, contributing to the ability of HPV-infected cells to evade ferroptosis and sustain tumor progression.