摘要Pharmaceutical formulations derived from Aristolochiaceae herbs,which contain aristolochic acids(AAs),are widely used for medicinal purposes.However,exposure to these plants and isolated AAs is linked to renal toxicity,known as AA nephro-pathy(AAN).Currently,the mechanisms underlying AAN are not fully understood,leading to unsatisfactory treatment strategies.In this study,we explored the protective role of 84-B10(5-[[2-(4-methoxyphenoxy)-5-(trifluoromethyl)phenyl]amino]-5-oxo-3-phenylpentanoic acid)against AAN.RNA-seq analysis revealed that the mitochondrion and peroxisome were the most affected cellu-lar components following 84-B10 treatment in AAN mice.Consistently,84-B10 treatment preserved mitochondrial ultrastructure,re-stored mitochondrial respiration,enhanced the expression of key transporters(camitine palmitoyltransferase 2)and enzymes(acyl-Coenzyme A dehydrogenase,medium chain)involved in mitochondrial fatty acid β-oxidation,and reduced mitochondrial ROS genera-tion in both aristolochic acid I(AAI)-challenged mice kidneys and cultured proximal tubular epithelial cells.Additionally,84-B10 treatment increased the expression of key transporters(ATP binding cassette subfamily D)and rate-limiting enzymes(acyl-CoA oxi-dase 1)involved in peroxisomal fatty acid β-oxidation and restored peroxisomal redox balance.Knocking down LONP1 expression di-minished the protective effects of 84-B10 against AAN,suggesting LONP1-dependent protection.In conclusion,our study provides evidence that AAN is associated with significant disturbances in both mitochondrial and peroxisomal functions.The LONP1 activator 84-B10 demonstrates therapeutic potential against AAN,likely by maintaining homeostasis in both mitochondria and peroxisomes.