Narrative review maps copper’s context-dependent role in oral fibrosis

A narrative review concludes that copper may have a context-dependent role in oral submucous fibrosis, a condition associated with the development of oral squamous cell carcinoma, but direct evidence that copper itself drives malignant transformation remains limited. The review, published in Molecular Biology Reports, examined literature concerning copper metabolism in oral submucous fibrosis and oral squamous cell carcinoma.

Oral submucous fibrosis is characterized by collagen accumulation and extracellular matrix deposition in the oral mucosa. The review identifies lysyl oxidase as a key mechanistic link: increased copper can enhance this enzyme’s activity, promoting greater collagen cross-linking. This process is consistent with the fibrosis seen in the condition. The authors describe copper as a contributor to the pathological environment rather than as a proven independent cause of malignancy.

Copper may also influence the cellular conditions that accompany fibrosis. Evidence summarized in the review indicates that excess copper can induce oxidative stress and epithelial injury. Together, these changes may create a microenvironment favorable to malignant transformation. However, the magnitude of these effects can vary with copper concentration, and the available findings do not establish a simple dose-response pathway from oral submucous fibrosis to oral squamous cell carcinoma.

At moderate elevations in intracellular copper, studies have associated copper with increased cellular proliferation, metabolic activity, and angiogenesis in oral squamous cell carcinoma. These are cellular and tumor-associated observations, not proof that copper produces the same effects in every patient or clinical setting. The review further notes that higher copper concentrations can be cytotoxic, suggesting that copper may shift from supporting proliferation and tissue remodeling to damaging cells when its intracellular level becomes sufficiently high.

The central limitation is the scarcity of direct evidence for copper-driven malignant transformation of oral submucous fibrosis. Most of the proposed connections are drawn from separate lines of research concerning collagen cross-linking, oxidative stress, epithelial injury, cancer-cell behavior, and angiogenesis. The narrative-review method synthesizes this literature but does not itself test causation, quantify risk, or demonstrate that a particular copper concentration predicts cancer. The findings therefore support continued investigation of copper homeostasis as a possible research avenue, including the development of candidate biomarkers and therapeutic strategies that adjust copper levels, while those clinical applications remain to be established.

Subject of Research: Copper metabolism in oral submucous fibrosis and malignant transformation

Article Title: Dual facets of copper in the malignant transformation of oral submucous fibrosis: A narrative review

Article References: S, G. P., Bose, D., Thayalan, D., AE, N., Krishnan, R., & A, R. (2026). Dual facets of copper in the malignant transformation of oral submucous fibrosis: A narrative review. Molecular Biology Reports, 53(1), Article 1505. https://doi.org/10.1007/s11033-026-12663-4

Image Credits: AI Generated

DOI: 10.1007/s11033-026-12663-4

Keywords: copper metabolism, oral submucous fibrosis, oral squamous cell carcinoma, collagen cross-linking, lysyl oxidase, oxidative stress, malignant transformation, angiogenesis, fibrosis, narrative review, Dual, facets