Hu Hua

The mode of electron transport in mitochondrial respiratory chain determines whether it generates energy or more reactive oxygen species (ROS), a key for cellular adaptation to diverse oxygen environments. However, the understanding of the mechanisms remains incomplete. Here, we find that NIMA-related kinase 7 (NEK7), targeted to mitochondria by its signal peptides, binds to succinate dehydrogenase complex iron sulfur subunit B (SDHB), stabilizing the spatial conformation of complex II and promoting forward electron transport. Deficiency of NEK7 in hepatocytes induces reverse electron transport (RET) and inhibits mitochondrial respiration, thereby promoting ROS generation, triggering spontaneous liver fibrosis and aggravating CCl ₄ -induced liver fibrosis, which can be attenuated by RET inhibitors. More importantly, NEK7 overexpression effectively alleviates CCl ₄ - and choline-deficient, high-fat diet-induced liver fibrosis. Overall, these findings highlight the pivotal role of NEK7 in orchestrating complex II and electron transport, providing new insights into the regulation of mitochondrial homeostasis and potential fibrosis treatments.

Background: The NLRP3 inflammasome is a cytoplasmic polymeric protein complex composed of the cytoplasmic sensor NLRP3, the apoptosis-related spot-like protein ASC, and the inflammatory protease caspase-1. NLRP3 activates and releases IL-1β through classical pathways, and IL-18 mediates inflammation and activates gasdermin-D protein to induce cellular pyroptosis. Numerous studies have also emphasized the non-classical pathway activated by the NLRP3 inflammasome in chronic kidney disease (CKD) and the inflammasome-independent function of NLRP3. Summary: The NLRP3-targeting inflammasome and its associated pathways have thus been widely studied in models of CKD treatment, but no drug that targets NLRP3 has thus far been approved for the treatment of CKD. Key Messages: We herein reviewed the current interventional methods for targeting the NLRP3 inflammasome in various CKD models, analyzed their underlying mechanisms of action, classified and compared them, and discussed the advantages and follow-up directions of various interventional methods. This review therefore provides novel ideas and a reference for the development of targeted NLRP3-inflammasome therapy in CKD.

Inflammation contributes to the pathogenesis of several diseases. Fenofibrate, known as a peroxisome proliferator-activated receptor - α (PPAR-α) agonist, is a classic drug for treating hyperlipidemia. In addition to its lipid-lowering effect, fenofibrate has also been reported to exert anti-inflammatory effects with complicated underlying mechanisms of action. In general, the anti-inflammatory effect of fenofibrate is secondary to its lipid-lowering effect, especially for the inflammation caused by hyperlipidemia in the circulatory system. Some anti-inflammatory actions may also come from its regulatory effects on intracellular lipid metabolism by activating PPAR-α. In addition, some roles in anti-inflammation might be mediated by its direct regulation of inflammatory signaling pathways. In order to understand anti-inflammatory activities and the underlying mechanisms of fenofibrate action in disease better, we herein reviewed and discussed the anti-inflammatory roles and its subserving mechanisms in various diseases of different organ systems. Thus, this review offers insights into the optimal use of fenofibrate in the clinical setting.