MG132

The proteasome inhibitor MG132 confirmed that fisetin accelerates β-catenin and MITF degradation. Additionally, inhibition of the PI3K/AKT pathway by LY294002 or the ERK pathway by PD98059 reversed fisetin's reduction of tyrosinase activity and melanin synthesis, further verifying the participation of these pathways. Computational docking integrated with deep learning-based CNN scoring revealed that fisetin interacts with PKCα, β-catenin, tyrosinase, and TYRP1. Collectively, these findings suggest that fisetin exerts multi-targeted inhibitory effects on melanogenesis, highlighting its potential as a therapeutic and cosmetic agent for hyperpigmentation.

Additionally, MG132 inhibited the differentiation of endothelial progenitor cells (EPCs) into smooth muscle cells (SMCs) and reduced the levels of inflammatory cytokines, including high-sensitivity C-reactive protein (hs-CRP), tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and interleukin-1 beta (IL-1β). Moreover, MG132 effectively suppressed the expression of NF-κB P65 and its downstream signaling pathway, intercellular adhesion molecule-1 (ICAM-1).

We constructed a RiskScore model for predicting the survival outcomes based on fibroblasts-related genes. These findings highlighted the role of fibroblasts in GBM development and offered six potential therapeutic targets (VWA1, DUSP6, LOXL1, IGFBP4, CYGB, and ZIC3) for GBM treatment. Additionally, immune infiltration analysis and drug sensitivity prediction further supported the model's utility in guiding personalized treatment of GBM.

Conversely, treatment with the proteasome inhibitor MG132 confirmed that rFIP-GMI stabilized cytoplasmic β-catenin phosphorylation and blocked its nuclear translocation. Collectively, these findings demonstrate that rFIP-GMI inhibits IGF-1-driven invasion and migration in TNBC by inactivating the PI3K/Akt/β-catenin axis, highlighting its potential as a therapeutic agent for this aggressive TNBC subtype.

Mechanistically, TPM3-TRKA degradation by compound 9 was dependent on CRBN-mediated polyubiquitination and proteasomal degradation; accordingly, it was hindered by inhibitors of the proteasome (MG132) or Cullins (MLN4924), by dominant negative Cullin 4A mutant, and by free pomalidomide. Finally, a compound 9 derivative, compound 20, induced in vivo degradation of TMP3-TRKA in KM12 cells mouse xenografts. In conclusion, our study indicated that PROTAC-mediated degradation is an efficient strategy to intercept RET and TRKA oncogenic signaling.

MEL suppresses the metastasis of NSCLC by targeting USP10 and promoting RNF20-mediated ubiquitination and degradation ofPSMA7.

After that, cells were treated with MG132, followed by analysis of the binding of TRAF6 to macrophage stimulating 1 (MST1) via co-immunoprecipitation and the ubiquitination level of MST1 via the ubiquitination assay...Silencing MST1 abolished the inhibition of TRAF6 on malignant proliferation of HANK1 cells. TRAF6 was upregulated in HANK1 cells and bound to MST1 to promote ubiquitination-mediated degradation of MST1, consequently facilitating the malignant proliferation of HANK1 cells.

SIN induced p65 ubiquitination and proteasomal degradation, as evidenced by cycloheximide/MG132 assays, thereby attenuating NF-κB signaling...In a rat CIBP model, SIN effectively alleviated mechanical allodynia and motor dysfunction, while downregulating nuclear factor κB activation and proinflammatory factor expression. These findings suggest SIN's dual therapeutic potential for simultaneous analgesia and anti-inflammatory effects in CIBP management.

Notably, KLHL13 downregulation induced by RHOBTB2 knockdown was reversed upon treatment with the proteasome inhibitor MG132, indicating that RHOBTB2 stabilizes KLHL13 by inhibiting its proteasomal degradation. Collectively, our findings highlight the RHOBTB2/KLHL13/Hippo pathway as a critical regulatory mechanism in AML malignancy and suggest RHOBTB2 as a potential therapeutic target.

Mechanistically, combined with enrichment analysis based on RNA sequencing, it was identified molecularly that UBE2S simultaneously inhibited the activation of MAPK/ERK and PI3K/AKT pathways through promoting the ubiquitin-mediated degradation of TRAF6 protein, an upstream molecule to activate the both pathways, which can be blocked by inhibitor MG132. Animal experiments demonstrated that knocking down UBE2S resulted in larger transplanted tumor volumes than the control group, while overexpressing UBE2S resulted in the smaller ones in vivo. Summarily, we firstly identified that the UBE2S inhibited CRC proliferation by negatively regulating MAPK/ERK and PI3K/AKT/mTOR pathways through ubiquitinating TRAF6 protein.

Rescue experiments with recombinant ubiquitin protein (Ub) and the ubiquitination inhibitor MG132 demonstrated that F-box and WD repeat protein 1A (FBW1A)-mediated ubiquitination of NLRP3 and C1qbp is required in TIPE2 deficiency-induced pyroptosis, mitochondrial damage and oxidative stress. Overexpression of TIPE2 suppressed NLRP3-mediated pyroptosis and C1qbp-mediated oxidative stress and improved respiratory function and pulmonary tissue damage in vivo. TIPE2 protects asthmatic bronchial epithelial cells from NLRP3-induced pyroptosis and C1qbp-induced oxidative stress by interacting with the E3 ubiquitin ligase FBW1A in vitro and in vivo.

Notably, the EPE-induced depletion of tyrosinase and TRP-1 was prevented by joint exposure to EPE and the proteasome inhibitor MG132...Immunoprecipitation analysis further revealed that EPE induces the ubiquitination of tyrosinase and TRP-1. Taken together, these results suggested that EPE induces proteasomal degradation of tyrosinase and TRP-1 by enhancing the ubiquitination of these targets, leading to the depletion of these proteins and the inhibition of melanogenesis.