Background and Purpose: Aristolochic acid nephropathy (AAN) is a progressive kidney disease caused by some herbal medicines, but treatment remains ineffective. We previously found NADPH oxidases 4 (NOX4), which regulates oxidative stress, play an important role in kidney injury model. However, its regulatory mechanism of action in AAN is still obscure. Experimental Approach: In this study, we established AAN model in vivo, a co-culture system of macrophage and TEC, and macrophage/TEC conditioned media culture model in vitro respectively. Key Results: We found macrophages infiltration promoted injury，oxidative stress and apoptosis of TEC. Furthermore, the role of macrophage in AAN was dependent on macrophages-derived EV. Importantly, we found that macrophages-derived, Leucine-rich α-2-glycoprotein 1(LRG1)-enriched EV induced TEC injury and apoptosis of via a TGFβR1-dependent process. Mechanistically, macrophages-derived, LRG1-enriched EV mediating TECs injury by upregulating NOX4 in AAN model. Conclusion and Implications: We identified EV as a potential link between macrophage-mediated inflammation and AAI-induced TEC oxidative stress and apoptosis. This study may help design a better therapeutic strategy to treat AAN patients.

Background and Purpose: Aristolochic acid nephropathy (AAN) is a progressive kidney disease caused by using herbal medicines. Currently, no therapies are available to treat or prevent AAN. Histone deacetylase (HDAC) plays a crucial role in the development and progression of renal disease. We tested whether HDAC inhibitors could prevent AAN and determined the underlying mechanism. Experimental Approach: HDACs expression in the kidneys was examined. Mouse kidney and renal tubular epithelial cell damage were assessed after exposure to HDAC1 and HDAC2 blockade (FK-228). Conditional knock-in of Proline-serine-threonine-phosphatase-interacting protein 2 (PSTPIP2) in the kidney and knockdown of PSTPIP2 expression in PSTPIP2-knockin mice, pathological parameters, and kidney injuries were assessed. Key Results: Aristolochic acid upregulated the expression of HDAC1 and HDAC2 in the kidneys. Notably, the HDAC1 and -2 specific inhibitor, romidepsin (FK228, Depsipeptide), suppressed aristolochic acid-induced kidney injury, epithelial cell pyroptosis, apoptosis, and necroptosis (PANoptosis). Moreover, romidepsin upregulated PSTPIP2 in renal tubular epithelial cells, which was enhanced by aristolochic acid treatment. Conditional knock-in of PSTPIP2 in the kidney protected against AAN. In contrast, the knockdown of PSTPIP2 expression in PSTPIP2-knockin mice restored kidney damage and PANoptosis. PSTPIP2 function was determined in vitro using PSTPIP2 knockdown or overexpression in mTEC. Additionally, PSTPIP2 was found to regulate Caspase-8 in Aristolochic acid nephropathy. Conclusion and Implications: HDAC-mediated silencing of PSTPIP2 may contribute to aristolochic acid nephropathy. Hence, HDAC1 and -2 specific inhibitors or PSTPIP2 could be valuable therapeutic agents for the prevention of aristolochic acid nephropathy.

Alcoholic steatohepatitis (ASH) is one of the predominant causes of liver-related morbidity and mortality worldwide. However, effective therapy for ASH is still lacking. Notably, increasing evidence indicates ferroptosis may counteract the injury of the ASH. We recently identified a novel strategy for attenuating ASH by an effective adjuvant via ferroptosis through targeting MDMX. Verbenalin, which is a major compound in Verbena officials L (Verbenaceae), is generally recognized as a kind of safe food by the U.S. Food and Drug Administration. In this study, we found for the first time that Verbenalin is protective against alcoholic liver injury through transmission electron microscopy, Fe2+ content detection and other research methods. Its effect can not only inhibit oxidative stress such as MDA, SOD, GSH, ROS, 4-HNE and other related indicators, but also inhibit the ferroptosis of hepatocytes caused by alcohol. It was further confirmed by computer docking that verbenalin was targeted to inhibit MDMX activity, promote PPAR-alpha activation, and inhibit alcohol-induced ferroptosis in hepatocytes. Hence, Verbenalin might be employed as a promising natural supplement for alcoholic liver injury drug therapy.