Caprin-1 silencing reverses YY1/HSP90α-mediated IDH1 stabilization to induce ferroptosis and sensitize cervical cancer to cisplatin

To clarify how Caprin-1 regulates cisplatin resistance in cervical cancer (CC) and to find related biomarkers. Tissues from 30 CC patients were analyzed. Caprin-1 and IDH1 expression was examined in cisplatin-sensitive and -resistant samples and cell lines (Hela/DDP, SiHa/DDP). The comprehensive analysis encompassed measuring viability via CCK-8, assessing cell death by propidium iodide staining, detecting ROS with 2′, 7′- dichlorodihydrofluorescein diacetate, quantifying the GSH/GSSG ratio, MDA, and Fe 2+ levels using biochemical kits, evaluating ferroptosis-related protein (GPX4, SLC7A11, FTH1) expression by Western blot, determining mitochondrial membrane potential (ΔΨm) with JC-1 staining, and observing ultrastructure via transmission electron microscopy. RNA immunoprecipitation (RIP), RNA pull-down, and actinomycin D assays tested Caprin-1 binding to YY1 mRNA. Dual-luciferase, chromatin immunoprecipitation, and RIP assays assessed YY1-mediated HSP90AA1 transcription. Co-IP verified HSP90α-IDH1 interaction. IDH1 modulation and Ferrostatin-1 treatment were evaluated in CAPRIN1-knockdown context. A xenograft model tested Caprin-1's effect on cisplatin response. Caprin-1 and IDH1 were upregulated in cisplatin-resistant samples. Silencing CAPRIN1 induced ferroptosis, as evidenced by increased levels of MDA, ROS, and Fe 2+ , decreased ΔΨm with concomitant morphological damage, and reduced ferroptosis-related proteins. It also increased cisplatin sensitivity. Caprin-1 bound and stabilized YY1 mRNA. YY1 activated HSP90AA1 transcription. HSP90α bound IDH1 and inhibited its degradation. IDH1 overexpression reversed ferroptosis and restored cisplatin sensitivity after CAPRIN1 knockdown; Ferrostatin-1 counteracted IDH1-silencing effects. In vivo, CAPRIN1 knockdown promoted ferroptosis, suppressed tumor growth, and synergized with cisplatin. Caprin-1 silencing enhances cisplatin sensitivity in CC by suppressing the YY1/HSP90α axis, accelerating IDH1 degradation, and activating ferroptosis. • Caprin-1 is upregulated in cisplatin-resistant cervical cancer (CC) tissues and cell lines. • Caprin-1 binds to and stabilizes YY1 mRNA. • YY1 binds to the HSP90AA1 promoter and promotes its transcription. • HSP90α stabilizes IDH1 by suppressing its ubiquitination and degradation. • Caprin-1 knockdown enhances cisplatin sensitivity in CC cells through ferroptosis induction.