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Updated: Jan 15, 2026
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Published on: March 15, 2024
CLDND1 as a prognostic ferroptosis-associated biomarker in oral squamous cell carcinoma
Xiaolong Zang1, Di Yan2, Yuxing Liu3
1Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Zhejiang Key Laboratory of Oral Biomedical, Hangzhou, 310000, China.
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.
