Investigation of the Hydrogen Sulfide Signaling Pathway in Schwann Cells during Peripheral Nerve Degeneration: Multi-Omics Approaches.

N -ethylmaleimide (NEM) inhibits peripheral nerve degeneration (PND) by targeting Schwann cells in a hydrogen sulfide (H 2 S)-pathway-dependent manner, but the underlying molecular and pharmacological mechanisms are unclear. We investigated the effect of NEM, an α,β-unsaturated carboxyl compound, on H 2 S signaling in in vitro - and ex vivo -dedifferentiated Schwann cells using global proteomics (LC-MS) and transcriptomics (whole-genome and small RNA-sequencing (RNA-seq)) methods. The multi-omics analyses identified several genes and proteins related to oxidative stress, such as Sod1 , Gnao1 , Stx4 , Hmox2 , Srxn1 , and Edn1 . The responses to oxidative stress were transcriptionally regulated by several transcription factors, such as Atf3 , Fos , Rela , and Smad2 . In a functional enrichment analysis, cell cycle, oxidative stress, and lipid/cholesterol metabolism were enriched, implicating H 2 S signaling in Schwann cell dedifferentiation, proliferation, and myelination. NEM-induced changes in the H 2 S signaling pathway affect oxidative stress, lipid metabolism, and the cell cycle in Schwann cells. Therefore, regulation of the H 2 S signaling pathway by NEM during PND could prevent Schwann cell demyelination, dedifferentiation, and proliferation.