Inflammatory and neurotoxic risk of atorvastatin in diabetic peripheral neuropathy: TNF-centered evidence integrating network toxicology, scRNA-Seq, and cell validation

Objective To clarify atorvastatin’s role in diabetic peripheral neuropathy (DPN) amid its controversial neuroprotective and neurotoxic effects. Methods Integrated network toxicology, single-cell RNA sequencing (scRNA-seq), molecular docking, molecular dynamics simulations, and in vitro assays (CCK-8, ELISA) on high-glucose-induced RSC 96 Schwann cells. Results Network toxicology identified TNF, CTNNB1, CASP3 as core targets (TNF as key hub), enriched in DPN-related pathways (oxidative stress, inflammation). scRNA-seq suggested that these targets are expressed in sensory neuron populations. Molecular docking and molecular dynamics simulations suggested that atorvastatin can interact with the selected targets, with relatively favorable predicted affinity for TNFα. In vitro , atorvastatin reduced cell viability in a time- and dose-dependent manner and was associated with increased TNFα levels under high-glucose conditions. Conclusion Our findings are consistent with a potential involvement of TNF/TNFα-associated inflammatory responses in atorvastatin-related cellular injury under the tested in vitro conditions. Further TNFα blocking/knockdown experiments will be needed to determine causality.