MG132 / Jilin University, Dorothy M. Davis Heart and Lung Research Institute - LARVOL DELTA

Revealing the Biochemical Regulations of L-PGDS in Hepatic Insulin-Resistance using HepG2 cells. (PubMed, Prostaglandins Other Lipid Mediat) - "To study this L-PGDS downregulation, we employed MG132, chloroquine, cycloheximide, and immunoprecipitation to assess proteasomal degradation, autophagy, translational activity, and ubiquitination, respectively. In summary, L-PGDS downregulation possibly involves transcription-translation and/or subcellular localization pathways. However, further studies are required to delineate the molecular mechanism of L-PGDS downregulation and apply this knowledge to MASLD pathogenesis and treatment."

Journal • Hepatology • Metabolic Disorders • Metabolic Dysfunction-Associated Steatotic Liver Disease • Targeted Protein Degradation

RNF20 promotes the progression of diffuse large B-cell lymphoma through regulating ubiquitination-dependent Phase separation of fus (ASH 2025) - "Furthermore, combined treatment of RNF20 deficiency and ibrutinib, a Bruton's tyrosine kinase inhibitor, significantly declined DLBCL cell proliferation compared to the control group...MG132 treatment reversed this effect, indicating proteasome involvement...In conclusion, our results revealed that RNF20 induced the ubiquitination-dependent phase separation of FUS, which promoted the malignant progression of DLBCL. This underscores the potential of RNF20 as a novel prognostic biomarker and therapeutic target for DLBCL."

B Cell Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Targeted Protein Degradation • FUS • RNF20

PARP1 facilitates transcriptional activity and stability of the BCL6 protein and is a therapeutic target in BCL6 expressing lymphomas (ASH 2025) - "While we showed that BCL6 is PARylated, BCL6 PARylation was not necessary for BCL6 TR,since reconstitution of PARP1 Crispr/Cas9-edited cells with wild type PARP1 or E988K PARP1 mutantsuppressed BCL6 reporter activity to levels observed in the non-manipulated 293T cells expressing BCL6.Since PARylation can regulate protein stability we performed cycloheximide (CHX) pulse-chaseexperiments showing progressive decrease in BCL6 protein levels over time, that was enhanced in thepresence of Olaparib and rescued by proteasome inhibitor MG132...Olaparib and Veliparib induced a pronounced decrease in colonyformation and cell viability as assessed by the MTS assay and potentiated similar effects of BCL6 inhibitor79-6. Both PARP1 inhibitors and BCL6 inhibitor 79-6 induced apoptosis and cell death in a cell line specificmanner. These combinations may be considered for clinical evaluation.Overall, for the first time our studies show that PARP1 plays an essential and direct role in..."

Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • BCL6 • MYC • PARP1

BTK regulates EZH2 stability in myeloid leukemia associated with down syndrome (ASH 2025) - "Although most ML-DS patients respond favorably to chemotherapy, outcomes remainpoor in relapsed or refractory cases, which highlights the need for novel therapeutic strategies.We previously demonstrated that dual inhibition of EZH2 and class I histone deacetylases (HDAC) byusing GSK126 and romidepsin synergistically suppressed ML-DS cell viability (Cicek et al., 2022)...Notably, BTK inhibition by Pirtobrutinib, a FDA-approved reversible BTK inhibitor,recapitulated the effects of combination treatment by reducing EZH2 protein level and inducing celldeath of relapsed ML-DS PDX cells via apoptosis. Proteosome inhibition with MG132 in the presence ofPirtobrutinib rescued EZH2 level, indicating that BTK inhibition reduces EZH2 stability via the ubiquitin-proteasome pathway. Furthermore, BTK inhibition suppressed key E2F-related oncogenic targets,including c-MYC, Bcl-xL and MCL-1, while upregulating the cell cycle inhibitor p21.Together, these findings highlight BTK as a novel..."

Acute Myelogenous Leukemia • Developmental Disorders • Genetic Disorders • Hematological Malignancies • Leukemia • Targeted Protein Degradation • ANXA5 • BCL2L1 • CASP3 • CASP7 • CD34 • GATA1 • MYC • RAD21 • STAG2 • SUZ12

Synergistic enhancement of APR-246 anti-leukemic activity through ENO1 inhibition in TP53- and FLT3-mutated Acute Myeloid Leukemia (ASH 2025) - "HighENO1 expression correlated with shorter OS in TP53-mutant (HR 2.14, p = 0.008) and FLT3-ITD (HR 1.87, p= 0.013) cohorts.Functional loss-of-ENO1: shENO1 reduced clonogenicity by 48–64 % and increased APR-246 sensitivity(IC50 fold-reduction: MOLM-13 2.9, Kasumi-1 2.3; ZIP synergy 29–43).Ferroptosis signature: Combined ENO1 inhibition plus APR-246 elevated lipid-ROS 3.7-fold, decreasedGSH by 62 %, and triggered mitochondrial shrinkage/cristae loss—phenotypes reversed by ferrostatin-1.Molecular mechanism: RNA-seq revealed selective down-regulation of the glutathione/ferroptosis axis.ENO1 interacted with the E3-ligase NEDD4L; ENO1 loss augmented NEDD4L-mediated poly-ubiquitination and proteasomal degradation of SLC7A11 and GPX4, whereas MG132 restored GPX4levels.Genotype independence: Synergy was observed irrespective of TP53 or FLT3 status, indicating a p53-independent metabolic vulnerability.ConclusionsENO1 is an adverse prognostic biomarker in AML whose enzymatic or..."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Targeted Protein Degradation • ENO1 • FLT3 • GPX4 • SLC7A11 • TP53

KMT2A::AF6 fusion protein localizes to PML nuclear bodies and undergoes ATO-induced degradation: A potential novel therapeutic approach for KMT2A::AF6-rearranged Acute Myeloid Leukemia (ASH 2025) - "Given that PML and its client proteins undergo proteasomal degradation upon arsenic trioxide(ATO) treatment via SUMO-dependent ubiquitination, we tested whether KMT2A::AF6 protein follows asimilar fate...Blocking the proteasomewith MG132 prevented this degradation, confirming that KMT2A::AF6, as well as PML, is degraded via theSUMO–ubiquitin–proteasome axis...This effect was partially reversed by N-acetylcysteine (NAC), suggesting a ROS-dependent mechanism, described to be the very first step by which ATO drives PML proteasomal-mediated degradation. Moreover, ATO treatment induced myeloid differentiation both in vitro and in exvivo patient-derived cells (PDXs), supporting a transcriptional change at support of a targeted KMT2A:.AF6fusion protein degradation mechanism.In vivo, ATO monotherapy (8 mg/kg) moderately delayed disease progression in KMT2A::AF6 PDX models,while its combination with low-dose cytarabine (20 mg/kg) significantly reduced leukemic burden andprolonged..."

Acute Myelogenous Leukemia • Acute Promyelocytic Leukemia • Hematological Malignancies • Leukemia • Targeted Protein Degradation • HOXA10 • HOXA11 • HOXA9 • KMT2A • RARA

Paralog interdependency between MEF2C and MEF2D sustains protein stability and leukemia maintenance in KMT2A-rearranged AML (ASH 2025) - "Proteasome inhibitor assays showed this degradation is prevented by MG132 treatment,implicating the ubiquitin-proteasome system...In a murine MLL-AF9 AML model, doxycycline-inducible expression of Peptide-54 significantly delayed diseaseprogression, reduced leukemia burden as assessed by bioluminescence imaging, and extended overallsurvival...We show that MEF2Dacts as a molecular chaperone to prevent CUL2-ZYG11B/ZER1-mediated degradation of MEF2C.Disrupting this interaction with a rationally designed competitive peptide induces degradation of bothparalogs, promotes differentiation, and suppresses AML progression in preclinical models. These findingshighlight a potential paradigm of transcription factor co-stabilization and suggest that targeting paraloginteractions may represent a therapeutically actionable vulnerability in high-risk leukemia."

Clinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Targeted Protein Degradation • CUL2 • KMT2A • MEF2C • MEF2D

The USP22-NAP1L1 deubiquitination axis in the pathogenesis of myelodysplastic syndromes (ASH 2025) - "The dynamics of NAP1L1ubiquitination-dependent degradation were further assessed using proteasome inhibitor MG132 andprotein synthesis inhibitor cycloheximide (CHX)... USP22 stabilizes the NAP1L1 protein through deubiquitination modification, therebypromoting the malignant progression of MDS. Targeting the USP22-NAP1L1 regulatory axis caneffectively inhibit disease progression, providing a potential novel therapeutic strategy for MDS."

Developmental Disorders • Hematological Malignancies • Myelodysplastic Syndrome • Solid Tumor • Targeted Protein Degradation • CD34 • NAP1L1 • USP22

Pathogenic variants at the N-terminal arginine residue 44 disrupt human GABA transporter 1 function: insights from Drosophila epilepsy models. (PubMed, Front Pharmacol) - "Proteasome inhibitors (MG-132, bortezomib) and the HDAC inhibitor trichostatin A (TSA) partially rescued R44Q function. Moreover, R44Q-expressing flies presented heat-induced seizures, which were mitigated by 4-phenylbutyrate (4-PBA) treatment. These findings elucidate the molecular basis of R44-mediated hGAT-1 dysfunction and highlight potential therapeutic avenues for SLC6A1-related neurodevelopmental disorders."

Journal • CNS Disorders • Developmental Disorders • Epilepsy • Psychiatry

The transcription factor ANAC017 links mitochondrial retrograde signaling with the ubiquitin-proteasome system to control mitochondrial function in Arabidopsis. (PubMed, Plant Commun) - "Loss of proteasome function through rpn1a mutation or MG132 treatment increased the abundance of TOM20 isoforms and induced mitochondrial stress marker genes...A second tier formed by ANAC053 and ANAC078 bound promoters of proteasome subunits, including RPN1a, and was required to restrain TOM20 accumulation. These findings establish a two step transcriptional circuit that engages the ubiquitin proteasome system to tune TOM abundance and coordinate protein import with organelle function."

Journal • Targeted Protein Degradation

Mechanistic Insights into Anti-Melanogenic Effects of Fisetin: PKCα-Induced β-Catenin Degradation, ERK/MITF Inhibition, and Direct Tyrosinase Suppression. (PubMed, Int J Mol Sci) - "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."

Journal • Dermatology • Dermatopathology • Melanoma • Oncology • Solid Tumor • Targeted Protein Degradation • CTNNB1 • MITF • Tyrosinase • TYRP1

NF-κB/ICAM-1 signaling regulates vascular dysfunction in depressive hypertension rats. (PubMed, Sci Rep) - "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)."

Journal • Preclinical • Cardiovascular • CNS Disorders • Depression • Hypertension • Oncology • Psychiatry • CRP • ICAM1 • IL1B • IL6 • RELA • TNFA

The ubiquitin system targets translocated EspH to proteasomal degradation. (PubMed, Gut Microbes) - "Moreover, we show that wild-type (EspHwt), but not the EspHK106R mutant, is subjected to degradation following translocation in an MG132-sensitive manner, indicating that the proteasome degrades the polyubiquitylated effector following translocation...These data reinforce the idea that EspH is polyubiquitylated and that the host proteasome degrades the translocated effector, possibly limiting its ability to toxicate the host cells. Additional implications of these effects on bacterial-host interactions are discussed."

Journal • Targeted Protein Degradation

Development of bifunctional PROTAC degraders targeting EGFR and immune microenvironment (ESMO-IO 2025) - "Co-treatment with proteasome (MG132) or E3 ligase inhibitors verified the ubiquitin-proteasome system dependency...In macrophages, E152 treatment downregulated M2 immunosuppressive markers (IL-10, TGF-β) and membrane expression of the immune checkpoint VISTA, indicating a shift from an immunosuppressive M2-like towards a pro-inflammatory M1-like phenotype.Conclusions This study successfully developed a novel bifunctional PROTAC capable of concurrently degrading EGFR in tumor cells and HRH1 in TAMs. This single-molecule approach achieves a "one-stone-two-birds" effect: directly inhibiting tumor cell growth via EGFR degradation and reprogramming the immunosuppressive TME by blocking HRH1-mediated M2 polarization.Legal entity responsible for the study The authors."

Oncology • EGFR • IL10 • TGFB1

Kelch-type F-box protein TaFBK34 improves wheat seedling tolerance to heat stress. (PubMed, BMC Biol) - "These findings show that TaFBK34 improves wheat tolerance to HS, at least in part through an interaction with the TaARL2 protein, and provides potential applications of these genes for the improvement of wheat."

Journal • ARL2

Study on the Mechanism of Aspirin Alleviating Kawasaki Disease With Coronary Artery Lesions by Inducing TRAF6 to Regulate STAT3 Ubiquitination and Inhibit Th17 Cell Differentiation. (PubMed, Drug Dev Res) - "Conversely, the effects of TRAF6 overexpression coupled with MG132 treatment on STAT3 expression were evaluated using RT-qPCR and western blot. TRAF6 facilitated the ubiquitination of STAT3, triggering its protein degradation, while UBE2N interacted with TRAF6 to modulate STAT3 expression. This study found that aspirin upregulates TRAF6 to ubiquitinate STAT3, inhibiting Th17 differentiation and improving KD with CAL."

Journal • Targeted Protein Degradation • CD4 • STAT3 • TRAF6

Discovery of a Proteolysis Targeting Chimera for TRKA and RET-derived oncoproteins. (PubMed, Sci Rep) - "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."

Journal • Colon Cancer • Colorectal Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • Thyroid Gland Carcinoma • Thyroid Gland Papillary Carcinoma • CCDC6 • CRBN • CUL4A • RET • TPM3

A fibroblast-specific gene signature as a therapeutic target for glioblastoma developed based on the characteristics of tumor microenvironment. (PubMed, Eur J Med Res) - "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."

Biomarker • Gene Signature • Journal • Brain Cancer • Glioblastoma • Oncology • Solid Tumor • DUSP6

rFIP-GMI Suppresses IGF-1-Induced Invasion and Migration in Breast Cancer Cells via PI3K/Akt/β-Catenin Inhibition. (PubMed, Drug Dev Res) - "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."

Journal • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • CCND1 • CTNNB1 • HER-2 • IGF1 • MMP9 • MYC

Mechanistic insights into NFIX frameshift mutations in Malan syndrome: proteasomal degradation-mediated haploinsufficiency. (PubMed, Front Genet) - "Analyzed degradation pathways using ubiquitin-proteasome inhibitor MG132 and autophagy-lysosome inhibitor Chloroquine (CQ). Results from protein degradation pathway analysis demonstrated that the truncated protein generated after mutation was degraded via the ubiquitin-proteasome pathway. The NFIX c.164delC p.Ala55Glyfs*2 frameshift mutation did not significantly affect mRNA expression levels, but induced protein degradation via the ubiquitin-proteasome pathway, resulting in haploinsufficiency and ultimately causing Malan syndrome."

Journal • Developmental Disorders • Infertility • Mental Retardation • Sexual Disorders • Targeted Protein Degradation

Multi-Omics and Molecular Dynamics Analysis for Biomarker Discovery in Chronic Rhinosinusitis With Nasal Polyps. (PubMed, Chem Biol Drug Des) - "Molecular docking and dynamics simulations established that the proteasome inhibitor MG132 can create a stable complex with PRKCZ...The current research demonstrates that alpha-toxin from Staphylococcus aureus promotes EMT in CRSwNP via the NF-κB/TGF-β signaling axis. A significant gene that may serve as a potential therapeutic target is PRKCZ."

Biomarker • Journal • Chronic Rhinosinusitis With Nasal Polyps • Immunology • Nasal Polyps • Otorhinolaryngology • Respiratory Diseases • Sinusitis • TGFB1

FBXW7 promotes osteoarthritis injury by regulating SLC7A11 ubiquitination degradation and chondrocyte ferroptosis. (PubMed, Pathol Res Pract) - "The ubiquitination degradation of SLC7A11 was accelerated by FBXW7 in chondrocytes, which was intercepted by MG132 treatment. In vivo experimental results further uncovered the alleviated functions of FBXW7 knockdown in ferroptosis and cartilage damage in OA model. The finding demonstrated that FBXW7 aggravated OA injury and ferroptosis, which might be linked to the ubiquitination degradation of SLC7A11."

Journal • Immunology • Osteoarthritis • Pain • Rheumatology • Targeted Protein Degradation • ADAMTS5 • FBXW7 • FER • GPX4 • SLC7A11

RSK1 Is an Exploitable Dependency in Myeloid Malignancies (ASH 2023) - P1/2 | "We further extended our findings to de novo AML harboring FLT3 internal tandem duplication (FLT3-ITD), where FLT3-ITD patients exhibited elevated RPS6KA1 expression, and those who developed resistance to gilteritinib demonstrated progressively increased RPS6KA1 expression...Through cycloheximide, MG-132, and ubiquitination assays, we found that RSK1 regulates FLT3-ITD activity and protein stability through deubiqutinase USP1, and where either RPS6KA1 or USP1 inhibition resulted in concomitant downregulation of FLT3 protein and cell lethality...Our findings uncover a novel therapeutic avenue for a conserved RSK1 dependency across chronic and acute myeloid neoplasms. The potent and consistent disease-ameliorating effects across numerous leukemia mouse models demonstrates promise for repurposing PMD-026 for the treatment of myeloid malignancies."

Acute Myelogenous Leukemia • Breast Cancer • Chronic Myelomonocytic Leukemia • Fibrosis • Hematological Malignancies • Immunology • Leukemia • Myelofibrosis • Myeloproliferative Neoplasm • Oncology • Solid Tumor • Targeted Protein Degradation • Triple Negative Breast Cancer • CCL3 • CCNA1 • CD14 • CD34 • CDK1 • CXCL8 • FLT3 • IL1B • IL6 • PTPRC • RELA • USP1

5-Methoxytryptophan attenuates hypobaric hypoxia induced acute lung injury by alleviating lipid peroxidation via targeting peroxiredoxin 6. (PubMed, Redox Biol) - "5-MTP is a predictive biomarker of hypoxic maladaptation. The restoration of 5-MTP attenuated ALI by inhibiting lipoperoxidation and protecting endothelial barrier via directly interaction with Ser32 site of Prdx6 to prevent its lysosomal degradation."

Journal • Acute Lung Injury • Respiratory Diseases • Targeted Protein Degradation • HIF1A • PRDX6

Fresh Ginseng Reduces Sphingosine Secretion Through Ubiquitin Degradation of SPTLC2 to Antagonize the Progression of Non-Small Cell Lung Cancer. (PubMed, Phytother Res) - "Western blot and RT-qPCR were used to verify its mechanism, Co-IP was used to detect SPTLC2 ubiquitination levels, and MG132 inhibition experiments were conducted to clarify the ubiquitin proteasome system (UPS) dependence and deepen the mechanism research...This study provides evidence that FG inhibits the progression of nonsmall cell lung cancer by targeting the SPTLC2-sphingosine axis, demonstrating its ability to specifically regulate sphingolipid metabolism with low toxicity. These findings support the potential of FG as a promising candidate therapeutic agent for nonsmall cell lung cancer."

Journal • Lung Cancer • Metabolic Disorders • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Targeted Protein Degradation