biostudies-literatureGong YNational Natural Science Foundation of ChinaShanghai Rising-Star ProgramShanghai Eastern Talent Programe13117https://www.ebi.ac.uk/biostudies/studies/S-EPMC12850329biostudies-literatureUnknown13(5)Exposure to aristolochic acids (AA) via the ingestion of AA-containing medicine or food is a significant risk factor for severe nephropathy. Despite decades of research, the direct molecular targets underlying AA toxicity remain elusive. In this study, a map of the AA-binding protein atlas in kidney tissues is constructed via the design and synthesis of an AA-based affinity probe. Among the AA-binding proteins, HIGD1A is identified as a high-affinity AA target (SPR: 59.6 nm; ITC: 195 nm) with significant thermostability changes upon AA binding. Furthermore, AA disrupted the HIGD1A-TFAM interaction, triggering TFAM degradation via the autophagy-lysosome pathway. This led to the accumulation of cytosolic mitochondrial DNA. This study also suggested that HIGD1A also contributed to AA-induced Advanced science (Weinheim, Baden-Wurttemberg, Germany)Affinity-Based Protein Profiling Revealed that HIGD1A is a Direct Target Protein of Aristolochic Acids.PMC128503298227191623QA141150082103885QNJY2024191QNWS2024063Wei ALuo ZMao GCen JZhang SGong YSun ZZhao XYin ZSun MChong XZou ZJi XZhang XPei ZMeng WQfalseAffinity-Based Protein Profiling Revealed that HIGD1A is a Direct Target Protein of Aristolochic Acids.Exposure to aristolochic acids (AA) via the ingestion of AA-containing medicine or food is a significant risk factor for severe nephropathy. Despite decades of research, the direct molecular targets underlying AA toxicity remain elusive. In this study, a map of the AA-binding protein atlas in kidney tissues is constructed via the design and synthesis of an AA-based affinity probe. Among the AA-binding proteins, HIGD1A is identified as a high-affinity AA target (SPR: 59.6 nm; ITC: 195 nm) with significant thermostability changes upon AA binding. Furthermore, AA disrupted the HIGD1A-TFAM interaction, triggering TFAM degradation via the autophagy-lysosome pathway. This led to the accumulation of cytosolic mitochondrial DNA. This study also suggested that HIGD1A also contributed to AA-induced 2026-01-01T00:00:00Z2026 Jan2026-06-16T07:22:07.834Z2026-06-16T03:09:51.401ZS-EPMC128503294119449210.1002/advs.202513117