Diabetic neuropathy and wound healing: An update on epigenetic crosstalk

Table 1 Key epigenetic regulators in diabetic neuropathy

Epigenetic factor	Evidence (model)	Clinical relevance/notes	Influence on DN	Influence on DFU	Interaction DN→DFU	Strength of evidence
DNMT1	High. Upregulated in diabetic macrophages/fibroblasts; also modulated by WTAP in HUVECs[3]	Drives pro-inflammatory macrophage phenotype in DFUs. Inhibitors (e.g., si-DNMT1) improve angiogenesis[3]	Possible (neuroinflammation via macrophages)	Yes (angiogenesis, inflammation)	Indirect via inflammation and repair	2+
TET2/NLRP3 (inflammasome)	Moderate. TET2 upregulation in DRG (mouse) causes demethylation and triggers TXNIP/NLRP3 pathway[40]	Linked to neuropathic pain. NLRP3 inhibitors are being explored in DN[3]	Yes (pain and inflammasome activation)	Limited evidence	Possible overlap via inflammasome	1+
HDAC1/3/4/11 (Class I HDACs)	Moderate. Overexpressed in DFU tissues; inversely correlates with Nrf2[13]	HDAC inhibitors (e.g., ricolinostat for HDAC6) have been trialed; isoform-specific HDAC inhibitors are under development[13]	Limited evidence in DN	Yes (angiogenesis, inflammation in DFUs)	Weak	1+
SIRT1 (Sirtuin deacetylase)	High. Downregulated in DFUs; deacetylates NF-κB and promotes antioxidant response[3]	SIRT1 activators (e.g., resveratrol, pterostilbene) improved angiogenesis/Nrf2 in DFU models[14,15]	Some evidence in DN (neuroprotection)	Yes (angiogenesis, healing)	Possible link through oxidative stress	2+
miR-146a	High. Anti-inflammatory miRNA. Promotes M2 macrophage polarization, accelerates healing[6]; ↓ in DRG of diabetic mice	Potential biomarker of DN severity; miR-146a mimic therapy improved wound healing in mice[6]	Yes (neuroinflammation, DRG changes)	Yes (wound healing, inflammation)	Yes (shared inflammation control)	2+
miR-155	High. Pro-inflammatory miRNA. Up in DFU wound fluid; its inhibition restores FGF7 and reduces inflammation[6]; down in some DN models	Anti–miR-155 (e.g., antagomir) could alleviate DFU inflammation[6]	Mixed (some DN models downregulated)	Yes (inflammation in DFUs)	Possible bidirectional	1+
miR-27b	Moderate. Regulates Nrf2/angiogenesis. Lower in chronic DFUs; Nrf2 activators restore miR-27b[29]	Candidate for miRNA therapy to boost Nrf2-mediated repair	Limited evidence in DN	Yes (angiogenesis in DFU)	Weak	1+
LncRNA NEAT1/miR-146a-5p	Emerging. NEAT1 down in DFUs → excess miR-146a-5p → suppressed mafG/angiogenesis[37,38].	Modulation of NEAT1 or miR-146a-5p is a novel target to restore DFU angiogenesis	Not yet established	Yes (angiogenesis defect in DFU)	Not known	neutral
lncRNA MALAT1	Moderate. Upregulated in DN; activates NLRP3 inflammasome and splicing defects[23]	lncRNA inhibitors (ASOs) could reduce neuroinflammation	Yes (neuroinflammation, splicing defects)	Limited	Weak	1+
circRNA_0002538	Moderate. ↓ in DPN. Binds miR-138-5p to upregulate PLLP (nerve repair)[33]	Potential biomarker (low in DPN) and therapeutic mimic (circRNA or target PLPP) to promote remyelination	Yes (nerve repair, remyelination)	Not yet studied	Not known	1+

ASO: Antisense oligonucleotide; circRNA: Circular RNA; DFU: Diabetic foot ulcer; DN: Diabetic neuropathy; DPN: Diabetic peripheral neuropathy; DRG: Dorsal root ganglion; HDAC: Histone deacetylase; HUVECs: Human umbilical vein endothelial cells; lncRNA: Long non-coding RNA; miR-/miRNA: MicroRNA; PLLP: Plasmolipin.