Adipoai: New Drug Inhibits Gingival Fibroblast Senescence To Alleviate Periodontitis

The progression of periodontitis is closely related to the senescence of human gingival fibroblasts (hGFs). The aim of this study was to elucidate the molecular mechanism by which AdipoAI, a novel lipocalin receptor agonist, inhibits the senescence of hGFs through activation of fatty acid oxidation (FAO) to alleviate periodontitis. Ligation-induced periodontitis model was constructed using 6-8 weeks old C57 mice, and cellular senescence model was established by LPS stimulation. The expression of senescence-associated secretory phenotypes (SASPs, such as IL-6, IL-8), senescence markers (p16, γH2AX) and fatty acid oxidation genes (CPT1A, ACSF2, ACADM) were detected by qRT-PCR, Western blot, β-galactosidase staining and other techniques. In animal experiments, periodontal tissue pathological changes and cellular senescence were assessed by micro-CT, HE staining, and immunofluorescence staining. AdipoAI significantly inhibited LPS-induced senescence of hGFs, as evidenced by the reduction of SA-β-gal activity and the down-regulation of p16 and γH2AX expression, as well as the up-regulation of fatty acid oxidizing genes, such as CPT1A, ACSF2 and ACADM. Local injection of AdipoAI attenuated periodontitis, decreased the levels of SASP factors (IL-6, IL-8), and inhibited SA-β-gal activity and expression of senescence markers in mice. Mechanistic studies showed that AdipoAI inhibited hGFs senescence by activating FAO through up-regulation of ACSF2, and its anti-senescence effect was reversed after ACSF2 knockdown. Our findings establish AdipoAI as a therapeutic agent targeting the ACSF2-FAO axis to suppress cellular senescence for periodontitis treatment.