Abstract
Chronic kidney disease (CKD) is closely associated with mitochondrial dysfunction, oxidative stress, and aging-related damage. CDGSH iron-sulfur domain-containing protein 2 (CISD2) plays a central role in mitochondrial homeostasis, calcium regulation, and cellular longevity, and its reduced expression has been linked to renal aging and CKD progression. In this study, an immunoinformatics-guided strategy was employed to identify small-molecule candidates capable of modulating CISD2 activity. A multi-step virtual screening pipeline-including drug-likeness filtering, absorption, distribution, metabolism, and excretion (ADME) prediction, molecular docking, and molecular dynamics simulations-was applied to an initial library of ~ 10,000 compounds. From this process, (2R)-2-[3,4-bis(oxidanyl)phenyl]-6-oxidanyl-2,3-dihydrochromen-4-one (6J6) emerged as the top candidate. 6J6 demonstrated favorable drug-like properties, strong predicted binding affinity, and stable interactions with the CISD2 binding pocket. Comparative analyses further suggest that 6J6 may offer advantages over known CISD2-targeting compounds such as hesperetin. KEGG-based pathway analysis indicated that CISD2 upregulation could promote mitochondrial biogenesis, reduce reactive oxygen species accumulation, and suppress inflammatory signaling, all of which are relevant to CKD. Unlike our earlier hesperetin-based study focused on liver aging, this work introduces 6J6 as a computationally identified for kidney disease, broadening the therapeutic scope of CISD2 modulation. These findings position 6J6 as a putative CISD2 modulator and provide a computational framework for advancing CKD drug discovery, though experimental validation remains necessary. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40203-025-00479-2.