Work

CLDND1 as a prognostic ferroptosis-associated biomarker in oral squamous cell carcinoma

Year: 2025

Type: article

Abstract: BACKGROUND: Oral squamous cell carcinoma (OSCC) lacks robust biomarkers to guide risk stratification and targeted therapy. Ferroptosis has emerged as a therapeutically actionable vulnerability, yet the role of claudin domain containing 1 (CLDND1) in OSCC and its connection to ferroptosis and tumor immunity remain unclear. METHODS: We integrated pan-cancer and OSCC-focused transcriptomic analyses from TCGA (ssGSEA, CIBERSORT, ESTIMATE; enrichment and network analyses) with survival modeling (Kaplan-Meier, LASSO, multivariable Cox; 1-year OS nomogram). Functional validation used WSU-HN30 and CAL 27 cells subjected to CLDND1 siRNA or ferroptosis activation (RSL3), followed by H&E, CCK-8, immunofluorescence, ELISA, and Western blot. RESULTS: CLDND1 was broadly upregulated across cancers and significantly elevated in HNSC/OSCC. High CLDND1 aligned with an immune-cold landscape (reduced cytotoxic/effector T-cell signals; enrichment of macrophage/resting compartments) and a ferroptosis-tolerant axis marked by positive associations with NFE2L2, SLC7A11, SLC3A2, and GPX4. Clinically, elevated CLDND1 predicted poorer disease-specific survival (HR ≈ 1.61) and overall survival (HR ≈ 1.51) and retained independent prognostic value in multivariable Cox analysis (HR ≈ 1.45). In vitro, CLDND1 knockdown reduced viability and proliferation, accompanied by morphological degeneration and decreased SRC, GPX4, SLC3A2, COL1, and KI67; RSL3 partially mimicked or enhanced these effects and lowered CLDND1 protein, indicating increased ferroptosis susceptibility upon CLDND1 suppression. CONCLUSIONS: CLDND1 marks an immune-cold, ferroptosis-resistant phenotype in OSCC and independently portends adverse outcomes. Targeting CLDND1-linked circuitry-alone or combined with ferroptosis induction-merits further translational evaluation for OSCC diagnosis and therapy.

Source: Biochemical and Biophysical Research Communications

DOI: 10.1016/j.bbrc.2025.152788