Background and purpose: Evidence indicates that ferroptosis plays a key role in acute kidney injury induced by cisplatin. The Nrf2/NRF2 pathway regulates oxidative stress, lipid peroxidation and positively regulates cisplatin-induced acute kidney injury, but its effect along with the alkaloid leonurine, found in motherwort, on ferroptosis after such acute kidney injury remains unclear.Experimental Approach: The anti-ferroptotic effects of Nrf2 and leonurine were assessed in a mouse model of cisplatin-induced acute kidney injury. In vitro, the effects of leonurine on erastin-and RSL3-induced HK-2 human PTEC ferroptosis were examined. Key Results: Nrf2 deletion induced ferroptosis-related protein expression and iron accumulation in vivo, aggravating cisplatin-induced acute kidney injury. Leonurine activated Nrf2 and prevented iron accumulation, lipid peroxidation and ferroptosis in vitro, being abolished in siNrf2-treated cells. Moreover, leonurine potently inhibited cisplatin-induced renal damage, as assessed by of serum creatinine, blood urea nitrogen, kidney injury molecule-1 and NGAL. Importantly, leonurine activated the Nrf2 antioxidative pathway and preventing changes in ferroptosis-related morphological and biochemical indicators, malondialdehyde level, SOD and GSH depletion, and GPX4 and xCT down-regulation, in cisplatin-induced acute kidney injury. Nrf2 KO mice were more susceptible to ferroptosis after cisplatin-induced acute kidney injury than control mice. The protective effects of leonurine on acute kidney injury and ferroptosis were largely abolished in Nrf2 KO mice. Conclusion and Implications: These data suggest that renal protective effects of Nrf2 activation on cisplatin-induced acute kidney injury are achieved, at least partially, by inhibiting lipid peroxide-mediated ferroptosis, highlighting the potential of leonurine in acute kidney injury treatment.

Previously, Our study has showed that farrerol can activate Nrf2 and ameliorate cisplatin-induced acute kidney injury (AKI). Mitophagy reportedly can prevent diabetic nephropathy, cisplatin-induced AKI and other related nephropathy. In this study, we evaluated the correlation between mitophagy and the protective effect of the Nrf2 activator farrerol on cisplatin-induced CKD by using C57BL/6 wild-type and Nrf2 knockout mice. We confirmed that Nrf2 and PINK1/Parkin-mediated mitophagy was significantly increased on the 3rd day of cisplatin stimulation but was reduced on the 38th day of cisplatin stimulation. Similar to previous results, farrerol activated Nrf2 on the 38th day of cisplatin administration, subsequently stimulating the Nrf2-targeted antioxidant enzymes HO-1 and NQO1. In addition, farrerol triggered PINK1/Parkin-mediated mitophagy by recruiting the receptor proteins LC3 and p62/SQSTM1, thereby eliminating damaged mitochondria. Furthermore, genetic deletion of Nrf2 reduced PINK1/Parkin-mediated mitophagy activation and led to increased renal tubular necrosis and renal fibrosis. We also found that farrerol alleviated inflammation and renal fibrosis by inhibiting p-NF-κB/NLRP3 and TGF-β/Smad signaling. These data indicated that farrerol effectively inhibited cisplatin-induced inflammation and renal fibrosis by activating Nrf2 and PINK1/Parkin-mediated mitophagy, which provides a potential novel therapeutic target for CKD.

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Background and purpose: Increasing evidence suggests that ferroptosis plays a key role in the pathophysiology of acute kidney injury induced by cisplatin. The Nrf2 signaling pathway regulates oxidative stress and lipid peroxidation and positively regulates cisplatin-induced AKI (CI-AKI). However, Nrf2 and its activator leonurine on ferroptosis after CI-AKI remain unclear. Experimental Approach: The anti-ferroptotic effects of Nrf2 and its activator leonurine were assessed using a mouse model of cisplatin-induced AKI. In vitro, the potential effects of leonurine on erastin- and RSL3-induced HK-2 human PTEC ferroptosis were examined. Key Results: As expected, Nrf2 deletion induced ferroptosis-related protein expression and iron accumulation in vivo, further aggravating CI-AKI. The Nrf2 activator leonurine prevented iron accumulation and lipid peroxidation and inhibited ferroptosis in vitro, while these effects were abolished in siNrf2-treated cells. Moreover, leonurine potently ameliorated cisplatin-induced renal damage, as indicated by the assessment of SCr, BUN, KIM-1, and NGAL. Importantly, leonurine activated the Nrf2 antioxidative signaling pathway and prohibited changes in ferroptosis-related morphological and biochemical indicators, such as the MDA level, SOD and GSH depletion and GPX4 and xCT downregulation, in CI-AKI. Moreover, Nrf2 KO mice were more susceptible to ferroptosis after CI-AKI than control mice, and the protective effects of leonurine on AKI and ferroptosis were largely abolished in Nrf2 KO mice. Conclusion and Implications: These data suggest that the renal protective effects of Nrf2 and its activator leonurine on CI-AKI are achieved at least partially by inhibiting lipid peroxide-mediated ferroptosis and highlight the potential of leonurine as a CI-AKI treatment.

Oxidative stress and inflammation play important roles in pleurisy. Leonurine (Leo) has been confirmed to exert antioxidative and antiinflammatory effects in many preclinical experiments, but these effects have not been studied in pleurisy. The aim of this study was to explore the therapeutic effect and mechanism of Leo in a carrageenan (CAR)‐induced pleurisy model. In this study, we found that the increase of reactive oxygen species (ROS), myeloperoxidase (MPO), and malondialdehyde (MDA) and decrease of glutathione (GSH) induced by CAR could be reversed by the treatment of Leo. Leo effectively reduced the levels of proinflammatory cytokines interleukin‐1β (IL‐1β), tumor necrosis factor‐α (TNF‐α), and the percentages of mature macrophages and increased the levels of antiinflammatory cytokines (IL‐10). Furthermore, Western blotting revealed that Leo significantly activated the Nrf2 pathway to restrain the thioredoxin‐interacting protein/NOD‐like receptor protein 3 (TXNIP/NLRP3) and nuclear factor kappa‐B (NF‐κB) pathways. However, the protective effect of Leo was significantly weakened in Nrf2‐deficient mice. These results indicate that Leo confers potent protection against CAR‐induced pleurisy by inhibiting the TXNIP/NLRP3 and NF‐κB pathways dependent on Nrf2, which may serve as a promising agent for attenuating pleurisy.