Exosomes derived from impaired liver aggravate alveolar bone loss via shuttle of Fasn in type 2 diabetes mellitus

Type 2 diabetes mellitus (T2DM) exacerbates irreversible bone loss in periodontitis, but the mechanism of impaired bone regeneration caused by the abnormal metabolic process of T2DM remains unclear. Exosomes are regarded as the critical mediator in diabetic impairment of regeneration via organ or tissue communication. Here, we find that abnormally elevated exosomes derived from metabolically impaired liver in T2DM are significantly enriched in the periodontal region and induced pyroptosis of periodontal ligament cells (PDLCs). Mechanistically, fatty acid synthase (Fasn), the main differentially expressed molecule in diabetic exosomes results in ectopic fatty acid synthesis in PDLCs and activates the cleavage of gasdermin D. Depletion of liver Fasn effectively mitigates pyroptosis of PDLCs and alleviates bone loss. Our findings elucidate the mechanism of exacerbated bone loss in diabetic periodontitis and reveal the exosome-mediated organ communication in the "liver-bone" axis, which shed light on the prevention and treatment of diabetic bone disorders in the future.