From Quiescence to Proliferation: Molecular Mechanisms Driving Malassez Epithelial Cell Activation and Proliferation Into Inflammatory Radicular Cystic Transformation

ABSTRACT Background Inflammatory radicular cysts (IRCs) arise from periapical granulomas (PGs). IRCs originate from Malassez epithelial remnants (ERMs), which can proliferate under specific biological stimuli. Although ERMs are common within PGs, only a subset of lesions evolves into IRCs, suggesting that specific molecular and immunoregulatory mechanisms govern this selective transformation. Objectives Molecular mechanisms and cellular signalling pathways modulating the epithelial proliferation of the ERM represent an inflexion point in the progression from PG to IRC. The objective of this review is to analyse the mechanisms and pathways involved in uncontrolled ERM proliferation, intending to elucidate why only a subset of epithelium‐containing PGs progress to IRCs. Methods A systematic literature search was conducted across MEDLINE (PubMed), Web of Science and Scopus from inception to July 2025. Sixty‐one articles met the inclusion criteria for narrative analysis and synthesis. Results ERM proliferation emerges from a coordinated interplay between immune, stromal and epithelial compartments. Fibroblast growth factor‐7 (FGF‐7/KGF) activates the FGFR2‐IIIb–MAPK/PI3K–AKT pathways, maintaining homeostasis of ERM proliferation. Transforming growth factor‐β (TGF‐β1/β2) and Smad2/3 signalling sustain epithelial quiescence. IGF‐BP‐6 sequesters bioavailable insulin growth factor (IGF‐II), avoiding mitogenic signalling. Proteolytic cleavage of IGF‐BP‐6 releases bioactive IGF‐II, enhancing ERM pathological proliferation. Intense AP upregulates epidermal growth factor (EGF) and its receptor (EGF‐R), promoting uncontrolled ERM proliferation. IL‐1β antagonises TGF‐β/Smad2 suppression through NF‐κB (p65) activation. IL‐6 promotes pathological ERM proliferation and migration via classic and trans‐signalling. Persistent M1 macrophage polarisation and Th1/Th17 dominance reinforce this microenvironment. Activated dendritic cells potentiate T‐cell responses and cytokine release. Conclusion Not all PGs progress to IRCs because cystic transformation requires the convergence of epithelial, stromal and immune thresholds that override ERM quiescence. This review proposes an integrative theoretical model that redefines ERMs as dynamic, inflammation‐responsive progenitors whose activation depends on immune–epithelial cross‐talk rather than infection alone. By delineating specific biomarker clusters—epithelial, immune/co‐stimulatory and stromal/remodelling—this work proposes a mechanistic framework capable of predicting lesion behaviour. It may establish the foundation for molecularly guided diagnosis and the rational design of targeted therapeutic strategies aimed at preventing or reversing cystic transformation, ultimately bridging molecular insight with clinical endodontic practice.