Role of immune dysregulation in aristolochic acid-induced multisystem toxicities: an insight from systems toxicology.

Exposure to aristolochic acids [AAs, including aristolochic acid Ⅰ (AAⅠ), aristolochic acid Ⅱ (AAⅡ), and aristololactam Ⅰ (ALⅠ)] has cast a shadow over public health due to the global therapeutic usage of the Aristolochiaceae herbs comprising AAs. Evidence is mounting that AAs exposure is definitely responsible for multisystem toxicities. The toxicological landscape of AAs, implicating toxic effects, toxicity targets, and toxicity signaling pathways, has yet to be thoroughly disentangled. We used the structure information of AAⅠ, AAⅡ, and ALⅠ to outline AAs multisystem toxicities. AAs targets were integrated to construct AAs-targets network and analyze their tissue and disease distribution. The intersections of AAs targets and the system-level toxicity targets were used for protein-protein interaction (PPI) analysis, core target identification, and functional annotation and enrichment analysis. We used two-sample Mendelian randomization (2SMR) to assess causal associations between the core targets and toxic effects. Molecular docking and molecular dynamics simulation (MDS) were applied to verifying the binding affinity of AAs with the core targets. AAs multisystem toxicities implicated renal, hepatic, neural, respiratory, reproductive, and hematic disorders. The network analysis with 2SMR evidence showed that TNF as the common target lay at the nexus of AAs multisystem toxicities. The signaling pathways underlying AAs toxic effects were functionally categorized as immune dysregulation, cell injury/apoptosis, abnormal blood supply, oxidative stress, and metabolic dysfunction. Immune dysregulation involved the shared signaling pathway "AGE-RAGE signaling pathway" that could trigger TNF overexpression and boost TNF signaling cascade. The profiling of AAs immunotoxic properties highlighted the essentiality of TNF and TNF signaling pathway in AAs-related immune dysregulation. The high-affinity binding of AAs to the core targets was illustrated via molecular docking and MDS. These findings demonstrate that immune dysregulation is instrumental in AAs multisystem toxicities. Disturbing AGE-RAGE axis and TNF signaling primes the hub mechanism of AAs toxic effects.