2. Academic Validation
  3. CLDND1 as a prognostic ferroptosis-associated biomarker in oral squamous cell carcinoma

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

  • Biochem Biophys Res Commun. 2025 Nov 1:787:152788. doi: 10.1016/j.bbrc.2025.152788.
Xiaolong Zang 1,  Di Yan 2,  Yuxing Liu 3,  Xiaojiao Sun 4,  Shouyi Zhang 5,  Xiaoxia Li 6,  Xing Wang 7
Affiliations

Affiliations

  • 1 Stomatology 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. Electronic address: [email protected].
  • 2 Department of Oral and Maxillofacial Surgery, General Hospital of Ningxia Medical University, Xingqing Block Shengli Street, Ningxia, YinChuan, 750004, China. Electronic address: [email protected].
  • 3 Ningxia Medical University, Xingqing Block Shengli Street, Ningxia, YinChuan, 750004, China. Electronic address: [email protected].
  • 4 Department of Oral and Maxillofacial Surgery, General Hospital of Ningxia Medical University, Xingqing Block Shengli Street, Ningxia, YinChuan, 750004, China; Ningxia Medical University, Xingqing Block Shengli Street, Ningxia, YinChuan, 750004, China. Electronic address: [email protected].
  • 5 Stomatology 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. Electronic address: [email protected].
  • 6 Stomatology 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. Electronic address: [email protected].
  • 7 Department of Stomatology, China Rehabilitation Research Center & Beijing Boai Hospital, Beijing, 100068, China. Electronic address: [email protected].
PMID: 41086680 DOI: 10.1016/j.bbrc.2025.152788
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.

Keywords

Bioinformatics; CLDND1; Ferroptosis; Oral squamous cell carcinoma (OSCC); Prognostic biomarker.

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