Background: Oral leukoplakia, the most common oral potentially malignant disorder (prevalence ~4.1%), transforms malignantly at a variable rate. Beyond tobacco and alcohol, chronic periodontal inflammation may co-modulate epithelial instability via pro-inflammatory cytokines (IL-6, TNF-α, IL-1β), oxidative stress, and dysbiotic pathogens (P. gingivalis, F. nucleatum), potentially synergizing with telomerase reactivation to drive malignant progression.

Objective: To explore the mechanistic interplay between chronic periodontal inflammation and telomerase activity in the initiation, persistence, and malignant progression of oral leukoplakia, emphasizing hTERT, oxidative stress, inflammatory signaling, genomic instability, and dysplasia.

Materials and Methods: A narrative review synthesizing clinical, molecular, experimental, and review literature on periodontitis, telomere biology, hTERT expression, inflammatory cytokines, and oral carcinogenesis was undertaken to construct a mechanistic framework.

Results: Periodontal inflammation fosters a pro-tumorigenic microenvironment via cytokine signaling and oxidative DNA damage, while telomerase/hTERT reactivation, positive in 31–60% of leukoplakia specimens, correlates with dysplasia severity and clinical subtype. Inflammatory mediators (ROS, IL-6, TNF-α, NF-κB) are plausible upstream activators of hTERT.

Conclusion: Periodontal inflammation and telomerase activity are mechanistically interlinked contributors to leukoplakia transformation, warranting combined risk-stratification approaches.

Keywords: Oral leukoplakia; Chronic periodontitis; Telomerase; Malignant transformation; Oral potentially malignant disorder; Chronic inflammation