Podophyllotoxin-induced acute kidney injury via the HMGB1/TLR4/MyD88/NF-κB axis in SD rats based on the toxicological evidence chain (TEC) concept via multiomic analysis

BACKGROUND: Podophyllotoxin (PPT) is a compound of significant clinical interest because of its anticancer properties; however, its systemic toxicity, particularly its nephrotoxicity, has not yet been fully elucidated. METHODS: Utilizing the toxicological evidence chain (TEC) approach, our team developed a rat model to investigate podophyllotoxin-induced acute kidney injury (AKI). Serum biochemistry and histopathology were used to assess systemic and renal toxicity. To explore underlying mechanisms, we performed 16S rRNA sequencing, Raman spectroscopy, and applied proteomic and metabolomic profiling. Key inflammation and cell death-related pathways were identified through integrated multi-omics analysis. RESULTS: Rats treated with podophyllotoxin presented manifestations of AKI, characterized by elevated serum creatinine and urea nitrogen levels, in conjunction with histopathological evidence. Additionally, dysregulation of oxidative stress markers and proinflammatory cytokines was observed. Through omic analysis, we identified significant metabolic disruptions and alterations in protein expression within the kidneys of rats subjected to PPT treatment. Notably, these changes were particularly evident in pathways associated with oxidative stress, inflammatory responses, and cell death mechanisms, including ferroptosis and lipid metabolism. Additionally, the pronounced reduction in the diversity of the gut microbiota, along with shifts in specific microbial taxa, indicates that PPT-induced renal injury may be closely linked to compromised gut barrier function and the exacerbation of systemic inflammation. CONCLUSION: Podophyllotoxin induces AKI through activation of the HMGB1/TLR4/MyD88/NF-κB signaling pathway. This study revealed HMGB1-mediated signaling as a key mechanism underlying the nephrotoxic effects of podophyllotoxin, identifying potential therapeutic targets to mitigate its toxicity and improve its clinical applicability.