Pepsin in Vocal Fold Leukoplakia: Pathobiological Role, Diagnostic Value, and Therapeutic Implications

BackgroundVocal fold leukoplakia (VFL) comprises a heterogeneous spectrum of epithelial lesions with variable risks of recurrence and malignant transformation. Laryngopharyngeal reflux (LPR) has increasingly been considered a chronic mucosal stressor in VFL, and pepsin has emerged as one of the most biologically relevant reflux-associated molecules.ObjectiveTo summarize current evidence on the pathobiological role of pepsin in VFL and to discuss its diagnostic and therapeutic relevance.MethodsA PRISMA-informed review was conducted using a prespecified PICO framework. PubMed, Web of Science, Embase, Google Scholar, and relevant gray-literature sources were searched from database inception to March 2026. Two reviewers independently screened records, extracted data, and assessed methodological quality using design-appropriate tools. The certainty of evidence was summarized using the GRADE framework. Owing to clinical, methodological, and outcome heterogeneity, formal meta-analysis was not performed.ResultsAvailable evidence suggests that pepsin may function not only as a marker of reflux exposure but also as an active mediator of epithelial injury. Tissue and translational studies indicate associations between pepsin-related reflux and epithelial barrier disruption, inflammatory infiltration, oxidative stress, autophagy, and metabolic reprogramming in vocal fold tissues. In VFL, tissue pepsin expression appears to increase with dysplasia severity, whereas salivary pepsin testing remains method-dependent and diagnostically inconsistent. Endoscopic morphology, vascular pattern assessment, and histopathology remain the core of risk stratification. Laser-based interventions continue to expand treatment options, but pepsin-directed management remains investigational.ConclusionsPepsin is a promising link between reflux biology and VFL progression, but the overall certainty of current evidence remains low to very low. At present, its main value lies in complementing established clinical and pathological assessment while refining mechanistic understanding of lesion behavior. Prospective studies integrating objective reflux testing, standardized pepsin measurement, advanced imaging, pathology, and longitudinal outcomes are needed before pepsin can be incorporated into routine clinical decision-making.