Germacrone Ameliorates Diabetic Kidney Disease by Activating TFEB to Promote Autophagy and Inhibit Inflammation

Diabetic kidney disease (DKD) is widely recognized as the primary cause of end-stage renal disease (ESRD). Activating autophagy is considered a key strategy to improve DKD. Here, through luciferase reporter gene screening of several sesquiterpenoids, it was found that germacrone (GER) significantly activated the transcription factor EB (TFEB), and its effect on DKD and the underlying molecular mechanism was investigated. GER significantly improved renal function impairment and alleviated renal pathological damage. GER inhibited NLR family pyrin domain containing 3 (NLRP3)-mediated inflammatory responses both <i>in vitro</i> and <i>in vivo</i>. Mechanistically, GER activated TFEB to promote autophagy and clear NLRP3 inflammasomes, and the GER-mediated degradation of NLRP3 was reversed by the autophagy inhibitor chloroquine (CQ). Additionally, GER did not affect the expression of TFEB protein but increased its expression in the nucleus. This effect was attributed to the dephosphorylation of p-TFEB (S122) protein caused by the activation of protein phosphatase 2A (PP2A) by GER. This result was further confirmed by supplementing with the PP2A inhibitor okadaic acid (OA). Docking results indicated a stable binding between GER and PP2A. These findings highlighted GER as a potential intervention for treating DKD and clarified the underlying mechanism through which it functions by regulating the PP2A-TFEB pathway.