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These conditions typically initiate in adulthood and progress chronically, often exhibiting severe manifestations. The socioeconomic impact is particularly acute in low\u2010 and middle\u2010income countries, where limited healthcare access exacerbates disease outcomes. Although conventional treatments provide symptomatic relief, they often fail to achieve complete tissue regeneration due to the complex pathophysiology of periodontal destruction. Mesenchymal stem cells (MSCs) have emerged as a transformative therapeutic strategy, demonstrating unique capabilities for immunomodulation, anti\u2010inflammatory effects, and multipotent differentiation. Preclinical studies have documented MSC\u2010mediated regeneration of periodontal ligaments, alveolar bone, and cementum through paracrine signaling and direct tissue integration. Clinical trials further substantiate their potential to improve key outcomes, including clinical attachment levels and probing depth reduction. However, five critical challenges require resolution for successful translation: (1) cellular source standardization, (2) mechanistic understanding of long\u2010term efficacy, (3) safety and immunological profiling, (4) ethical and economic barriers, and (5) clinical translation barriers. This review systematically evaluates current evidence on MSC\u2010based periodontal regeneration, analyzes these translational challenges, and provides strategic guidance for future research. 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