Post-translational modifications in the oral microenvironment: Stem cell regulation from periodontal regeneration to oral cancer therapy

Table 1 Dental-derived stem-cell types and post-translational modification signatures

Stem-cell type	Tissue source	Dominant PTMs reported	Key regulatory enzymes	Regenerative potency	Ref.
PDLSCs	Periodontal ligament	Histone H3K9/H3K14 acetylation; m6A RNA methylation; K48-linked ubiquitination	GCN5 (HAT); METTL3 (m6A writer); Smurf1 (E3 ligase)	High-drives alveolar bone, cementum and ligament regeneration	[7,24,36,41]
DPSCs	Dental pulp (dentin-pulp complex)	m6A RNA methylation; histone H3K27/H3K9 acetylation; p38/JNK phosphorylation	METTL3 (m6A writer); p300/GCN5 (HATs); p38 MAPK (kinase)	High-supports dentin-pulp repair and neurovascular regeneration	[10,25,26,29,43]
SCAPs	Apical papilla of immature permanent teeth	m6A RNA methylation; stage-specific H3K9 acetylation	METTL3 (m6A writer); HAT (e.g., GCN5)	Very high-promotes root development, angiogenic osteogenesis	[40,50,51]

PTM: Post-translational modification; PDLSCs: Periodontal ligament stem cells; DPSCs: Dental pulp stem cells; SCAPs: Stem cells from the apical papilla; m6A: N6-methyladenosine; JNK: C-Jun N-terminal kinase; GCN5: General control non-depressible 5; METTL3: Methyltransferase-like 3; MAPK: Mitogen-activated protein kinases; HAT: Histone acetyltransferase.

Table 2 Post-translational modification signatures in malignancy-associated dental stem-cell populations

Stem-cell type	Tissue source	Dominant PTMs reported	Key regulatory enzymes	Regenerative potency/tumorigenic capacity	Ref.
OCSCs (CD44+/ALDH1+)	Primary OSCC tumour tissues & spheres	m6A RNA methylation; H3K27 trimethylation; K63/K48-linked ubiquitination; STAT3 Tyr705 phosphorylation	METTL3; EZH2; Skp2; STAT3	High tumour-initiation, chemoresistance, EMT plasticity	[59,76,82-84]
Inflammation-transformed PDLSCs	Chronic periodontitis-affected periodontal ligament	H3K27 trimethylation; H3K9 acetylation imbalance; Smurf1-mediated ubiquitination	EZH2; GCN5; Smurf1	Diminished osteogenic potential; pro-malignant phenotypes	[27,36,41,105]

PTM: Post-translational modification; OCSCs: Oral cancer stem cells; ALDH: Aldehyde dehydrogenase; PDLSCs: Periodontal ligament stem cells; OSCC: Oral squamous cell carcinoma; K63/K48: Lysine-63/-48-linked polyubiquitin; STAT3: Signal transducer and activator of transcription 3; METTL3: Methyltransferase-like 3; EZH2: Enhancer of zeste homolog 2; Skp2: S-phase kinase-associated protein 2; GCN5: General control non-depressible 5; EMT: Epithelial-mesenchymal transition.