PPP1R15A

Copper ions play a crucial role as cofactors for essential enzymes in cellular processes. However, when the intracellular concentration of copper ions exceeds the homeostatic threshold, they become toxic to cells. In our study, we demonstrated that elesclomol, as a carrier of copper ions, caused an upregulation of protein phosphatase 1 regulatory subunit 15 A (PPP1R15A), which plays a role in regulating substrate selectivity of protein phosphatase 1 during cuproptosis. Mechanistically, we investigated that PPP1R15A activated translation initiation by dephosphorylating eukaryotic translation initiation factor 2 subunit alpha at the S51 residue through protein phosphatase 1 and phosphorylating eukaryotic translation initiation factor 4E binding protein 1 at the T70 residue. In addition, PPP1R15A reduced H3K4 methylation by altering the phosphorylation of histone methyltransferases, which led to the silencing of MYC and G2M phase arrest.

This study investigated the underlying comorbidity mechanism between type 2 diabetes mellitus (T2DM) and osteoarthritis (OA), while also assessing the therapeutic potential of quercetin for early intervention and treatment of these two diseases. The shared genes were obtained through GEO2R, limma and weighted gene co-expression network analysis (WGCNA), and validated using clinical databases and the area under the curves (ROC). Functional enrichment analysis was conducted to elucidate the underlying mechanisms of comorbidity between T2DM and OA. The infiltration of immune cells was analysed using the CIBERSORT algorithm in conjunction with ESTIMATE algorithm. Subsequently, transcriptional regulation analysis, potential chemical prediction, gene-disease association, relationships between the shared genes and ferroptosis as well as immunity-related genes were investigated along with molecular docking. We identified the 12 shared genes (EPHA3, RASIP1, PENK, LRRC17, CEBPB, EFEMP2, UBAP1, PPP1R15A, SPEN, MAFF, GADD45B and KLF4) across the four datasets. Our predictions suggested that targeting these shared genes could potentially serve as therapeutic interventions for both T2DM and OA. Specifically, they are involved in key signalling pathways such as p53, IL-17, NF-kB and MAPK signalling pathways. Furthermore, the regulation of ferroptosis and immunity appears to be interconnected in both diseases. Notably, in this context quercetin emerges as a promising drug candidate for treating T2DM and OA by specifically targeting the shared genes. We conducted a bioinformatics analysis to identify potential therapeutic targets, mechanisms and drugs for T2DM and OA, thereby offering novel insights into molecular therapy for these two diseases.