RNA-seq analyses of human periodontal ligament fibroblasts (PDLF) stimulated with GNE495 and FGF-2

Outcomes included cementoenamel junction–alveolar bone crest (CEJ–ABC) distance and bone volume fraction. Transcriptome and protein analyses probed the mechanisms of action using the SREBP inhibitor PF-429242 with cyclin D1 (CCND1) readouts. GNE-495 increased PDLF proliferation without loss of mineralization.

In mice, GNE-495 accelerated periodontal tissue regeneration. FGF-2 co-administration produced greater regeneration than either agent alone. In vitro, FGF-2 modestly accelerated early proliferation but reduced alkaline phosphatase (ALP).

Combined with GNE-495, it produced a sustained proliferative gain, which is consistent with an immature, pro-regenerative phenotype. RNA sequencing revealed the enrichment of lipid metabolic programs and SREBP1 signaling with GNE-495, which was potentiated by FGF-2. SREBP1 protein levels increased with GNE-495 ± FGF-2, and SREBP blockade reduced proliferation and CCND1 induction.

Local MAP4K4 inhibition promotes PDLF proliferation and periodontal tissue regeneration, and FGF-2 amplifies these benefits synergistically. Targeting MAP4K4 alone or with FGF-2 emerges as a promising strategy for periodontal regeneration by engaging an SREBP1-CCND1-linked lipid metabolic program.