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 in vitro and in vivo. 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.
Yunguang Wang,Shaoting Wang,Qikai Luo,Yourou Zhou,Xingchen Li,Yiwei Shang,HuaiYu Wang,Egor Y. Plotnikov,Xinyu Liao,Wei Feng,Qiang He,Juan Jin
Acute kidney injury (AKI) is a life-threatening clinical syndrome marked by a rapid decline in renal function, contributing to substantial morbidity and mortality. Emerging evidence suggests that modulating macrophage polarization represents a promising therapeutic strategy for AKI. However, achieving precise pharmacological regulation remains a challenge. To address this, we developed a novel macrophage-targeting nanoplatform (GMO@GO@PEG@MAN) by loading germacrone onto mannose-functionalized graphene oxide nanosheets. This engineered system enhances renal accumulation and enables macrophage-specific delivery in AKI models, while significantly suppressing pro-inflammatory M1 macrophage polarization. It provides multi-mechanistic renal protection by attenuating oxidative stress, promoting NRF2 nuclear translocation, inhibiting ferroptosis, and exerting potent broad-spectrum antimicrobial activity against both extracellular and intracellular pathogens. Our findings establish this nanoplatform as an effective multi-targeted therapy for AKI, demonstrating robust efficacy across both in vitro and in vivo models. This synergistic therapeutic strategy—combining macrophage reprogramming, oxidative stress mitigation, and antimicrobial activity—marks a significant advancement in AKI treatment paradigms.
危险品化学品经营许可证（带存储）