AMPK Modulates the Interplay Between PINK1 /Parkin‐Mediated Mitophagy and NLRP3 ‐Driven Inflammation in Diabetic Periodontal Tissue Under Mechanical Loading

ABSTRACT Mechanical force induces a series of biological responses such as inflammation in force‐loaded tissues and cells. The periodontal ligament (PDL) fibroblasts act as vital sensors and transducers in response to mechanical loading within periodontium. Studies have shown that PDL fibroblasts also participate in mediating periodontal inflammatory responses under physiological or pathological conditions. Mitophagy is a selective form of autophagy that eliminates damaged or dysfunctional mitochondria to maintain cellular health. It plays a vital role in inflammation alleviation, cell survival, and tissue homeostasis. However, whether mitophagy is involved in mechanical force‐related inflammation and the precise mechanisms remain unclear. In addition, the elucidation of the interplay between mitophagy and periodontal inflammation during mechanical loading is of great significance for maintaining periodontal homeostasis under systemic conditions. In our study, we first focused on validating the crosstalk between mitophagy and inflammation in PDL fibroblasts under mechanical loading and aimed to elucidate the upstream regulatory role of adenosine monophosphate‐activated protein kinase (AMPK). Moreover, based on both in vivo and in vitro experiments, we found that high glucose conditions exacerbated inflammation by suppressing mitophagy. Additionally, targeted activation of AMPK enhanced mitochondrial turnover through mitophagy, thereby disrupting proinflammatory cascades and offering a promising strategy for inflammation resolution in periodontal diseases, especially those combined with diabetic conditions.