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Diabetic peripheral neuropathy (DPN) is a chronic complication associated with nerve dysfunction and uncontrolled hyperglycemia. Unfortunately, due to its complicated etiology, there has been no successful therapy for DPN. Our research recently revealed that jatrorrhizine (JAT), one of the active constituents of Rhizoma Coptidis, remarkably ameliorated DPN. This work highlighted the potential mechanism through which JAT relieves DPN using db/db mice. The results indicated that JAT treatment significantly decreased the threshold for thermal and mechanical stimuli and increased nerve conduction velocity. Histopathological analysis revealed that JAT significantly increased the number of sciatic nerve fibers and axons, myelin thickness, and axonal diameters. Additionally, JAT markedly elevated the expression of myelination‐associated proteins (MBP, MPZ, and Pmp22). The screening of histone deacetylases (HDAC) determined that histone deacetylase 3 (HDAC3) is an excellent target for JAT‐induced myelination enhancement. Liquid chromatography–mass spectrometry—(MS)/MS and coimmunoprecipitation analyses further confirmed that HDAC3 antagonizes the NRG1‐ErbB2‐PI3K‐AKT signaling axis by interacting with Atxn2l to augment SCs myelination. Thus, JAT ameliorates SCs myelination in DPN mice via inhibiting the recruitment of Atxn2l by HDAC3 to regulate the NRG1‐ErbB2‐PI3K‐AKT pathway.

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Background Hepatocellular carcinoma (HCC) is a leading cause of death in humans. Clinical investigations have reported that insulin-like growth factor 2 (IGF2) mRNA binding protein 1 (IGF2BP1) is overexpressed in HCC, promoting oncogene activation, and is associated with cancer progression and poor prognosis. Previous research from our laboratory found that coptisine (COP) could inhibit the proliferation of HCC cells, but the exact mechanism was unknown. Methods The activity of COP against HCC was evaluated by the experiments with HCC cells and HuH7 xenografted mice. Based on transcriptome analysis, cellular thermal shift assay (CETSA), and mass spectrometry analysis, the key direct target of COP in inhibiting the proliferation of HCC were discovered. In vitro and in vivo assays were performed to study the biological function of IGF2BP1 in HCC. Screening of E3 ligases and deubiquitin enzyme interacting with IGF2BP1 by IP-mass spectrometry and website prediction. The molecular mechanism of COP causes protein ubiquitination and degradation of IGF2BP1 was demonstrated by CO-IP, immunofluorescence and protein stability assays. Result The results disclosed that COP could inhibit the growth of liver cancer cells and tumors and IGF2BP1 was identified as the direct target of COP. IGF2BP1 overexpression and silencing in vivo and in vitro confirmed that IGF2BP1 could significantly influence the growth of liver cancer cells and tumors. Mechanistic studies revealed that COP could either increase the interaction between E3 ligase Pre-mRNA Processing Factor 19 (PRPF19) and IGF2BP1 or decrease the deubiquitin function of the deubiquitin enzyme Ubiquitin Specific Peptidase 10 (USP10), resulting in increased ubiquitin degradation of IGF2BP1. Conclusions These findings suggest that COP has an anti-HCC activity by reducing IGF2BP1 expression. It opens up new avenues for research into modern pharmacology and the molecular mechanisms of traditional Chinese medicine against tumors.