bims-midomi 2025-11-30 papers

bims-midomi

Biomed News

on MDM2 and mitochondria

Issue of 2025–11–30
eleven papers selected by
Gavin McStay, Liverpool John Moores University

MDM2 in the signaling pathways related to neurological diseases.
NF1 Mutated Gastrointestinal Stromal Tumors With Coamplification of MDM2 and MYC.
Dysfunction of the Autophagy System and MDM2-p53 Axis Leads to the Accumulation of Amyloidogenic Proteins in Angelman Syndrome Models.
Regulatory role of sirtuin-1 by targeting MDM2 to mitochondria-associated membranes formation in the treatment of NAFLD.
Anticancer activity of MDM2 inhibition in 2D and bioprinted 3D retinoblastoma cell models.
Helicobacter pylori Lipopolysaccharide Upregulates MDM2 via the TLR4/MAPK/AP-1 Pathway to Promote Gastric Cancer Progression.
The Association and Significance of MDM2 and NF-κB Protein Expression in Multiple Myeloma.
Genetic Polymorphism of MDM2 Gene Associates with Breast Cancer Incidence in the Lower Northern Thailand.
MDM2-amplified esophageal adenocarcinomas exhibit an activated metabolic and immunosuppressive phenotype with multiple potential therapeutic targets.
EGCG inhibits hepatic stellate cell activity and liver fibrosis by targeting the MDM2/MUC5AC-mediated TGF-β1/Smad signaling pathway.
A triple-action PROTAC for wild-type p53 cancer therapy.

Neurobiol Dis. 2025 Nov 21. pii: S0969-9961(25)00417-6. [Epub ahead of print]217 107200

MDM2 in the signaling pathways related to neurological diseases.

Caizhen Shi, Yajuan Xue, Jiawen Li, Danni Hui, Bingbing Wang, Shenghao Qian, Li Dan, Yanjie Guo, Yan Fan, Juan Shen, Yanling Yang, Kunpeng Jia, Lin Zhao.

  Mouse double minute 2 homolog (MDM2) is a key negative regulator of the p53 pathway, functioning through its E3 ubiquitin ligase activity to control cell-cycle progression, DNA damage response, and apoptosis. Recent findings reveal that MDM2 also plays multifaceted roles in the central nervous system (CNS), extending beyond its canonical oncogenic functions. Increasingly, MDM2 has been implicated in the pathogenesis and progression of neurodegenerative diseases, brain injury, neuroinflammation, and cognitive dysfunction.This review integrates current advances on the non-canonical roles of MDM2 in CNS disorders, focusing on its involvement in mitochondrial homeostasis, autophagy regulation, synaptic plasticity, immune modulation, and metabolic signaling. Unlike previous reviews that addressed MDM2 mainly in oncogenesis or single neurological conditions, this work establishes a stage- and cell-type-specific framework of MDM2 regulation within the CNS. It distinguishes p53-dependent stress-surveillance mechanisms from p53-independent repair and metabolic pathways and introduces a therapeutic-window concept that balances neuroprotection with adaptive stress responses.Together, these perspectives position MDM2 as a dynamic molecular switch orchestrating neuronal fate, providing conceptual foundations for context-specific therapeutic strategies in neurological disease.

Keywords:  Autophagy; CNS diseases; MDM2; Mitochondria; Therapeutic target; p53

DOI:  https://doi.org/10.1016/j.nbd.2025.107200
Genes Chromosomes Cancer. 2025 Nov;64(11): e70096

NF1 Mutated Gastrointestinal Stromal Tumors With Coamplification of MDM2 and MYC.

Xinyang Chen, Yang Lu, Xin He, Du He, Min Chen, Hongying Zhang.

  We report a unique case of a 57-year-old man with a gastrointestinal stromal tumor (GIST) that developed a high-grade phenotype and additional genetic alterations in the subsequent recurrence. Histologically, the initial resected tumor showed a typical morphology with uniform spindle-shaped cells arranged in fascicular and whorling patterns. However, based on large tumor size and mitotic activity it was designated as high risk. Tumor cells were immunoreactive for CD117 and DOG1. Mutational analysis identified no KIT or PDGFRA hotspot mutations. Next-generation sequencing (NGS) further demonstrated an NF1 mutation (c.1466A>G) without KIT or PDGFRA mutations. In contrast, the recurrent tumor displayed a higher-grade morphology. Tumor cells were positive for MDM2, while showing decreased expression for CD117 and DOG1. NGS and molecular assays detected no KIT or PDGFRA mutations, but confirmed the NF1 mutation (c.1466A>G). In addition, NGS identified MDM2 and MYC amplification. This is the first report describing an NF1-mutant GIST harboring coamplification of MDM2 and MYC and associated with a higher-grade tumor progression.

Keywords:  MDM2 amplification; MYC amplification; NF1 mutation; gastrointestinal stromal tumors; higher‐grade transformation; tumor progression

DOI:  https://doi.org/10.1002/gcc.70096
Int J Mol Sci. 2025 Nov 14. pii: 11032. [Epub ahead of print]26(22):

Dysfunction of the Autophagy System and MDM2-p53 Axis Leads to the Accumulation of Amyloidogenic Proteins in Angelman Syndrome Models.

Jacqueline Fátima Martins de Almeida, Martina Contestabile, Ilaria Tonazzini, Chiara De Cesari, Laura Baroncelli, Claudia Martini, Simona Daniele.

  Angelman Syndrome (AS) is a neurodevelopmental disorder caused by the deficiency of the UBE3A gene that for a E3 ligase protein part of the ubiquitin-proteasome system (UPS). Autophagy and UPS systems remove abnormal proteins, but any dysfunction in these processes can affect neuronal development and wellbeing. Herein, the involvement of the UPS/autophagy system in the regulation of intracellular signaling pathways related to toxic protein accumulation was investigated in cellular/mice AS models, silenced for UB3A (UB3A-). The main findings are as follows: (i) autophagy was upregulated in UBE3A- cells with respect to control cells; (ii) a dysregulation of the AKT/mTOR pathway, linked to autophagy/synaptic development, was evidenced in cellular/animal models of AS with respect to controls; (iii) the ubiquitin ligase MDM2 was downregulated, and the tumor suppressor p53, normally inhibited by MDM2, enhanced its expression and transcriptional activity in UB3A- cells with respect to controls. Finally, UB3A- cells presented a significant alteration in the levels of β-amyloids with respect to control cells, and a reduction of α-synuclein levels, typical of neurodevelopmental disorder. Nevertheless, UB3A- cells do not show evident morphological abnormalities. Overall, these data suggest that AS models presented an altered signaling pathway related to autophagy/UPS systems, potentially leading to the accumulation of toxic proteins affecting synaptic development.

Keywords:  Angelman syndrome; amyloid proteins; autophagy; protein accumulation; ubiquitin–proteasome system

DOI:  https://doi.org/10.3390/ijms262211032
Cell Commun Signal. 2025 Nov 28. 23(1): 514

Regulatory role of sirtuin-1 by targeting MDM2 to mitochondria-associated membranes formation in the treatment of NAFLD.

Rui Zhang, Quanwei Zhang, ZiYi Cui, BenZeng Huang, Manman Li, Haitian Ma.

  Non-alcoholic fatty liver disease (NAFLD) is a common liver disorder characterized by excessive fat accumulation in the liver. Aberrant enrichment of mitochondria-associated membranes (MAMs) plays a significant role in promoting the overproduction of reactive oxygen species (ROS). However, the precise role of MAMs in NAFLD and the potential targets regulating MAMs formation remain unclear.This study demonstrated that SIRT1 inhibits abnormal MAM enrichment in the livers of NAFLD mice and PA-incubated hepatocytes. Moreover, the protective effects of SIRT1 against NAFLD caused by excessive caloric intake are closely associated with its ability to block MAMs-induced mitochondrial Ca2⁺ overload. This regulation alleviates Ca2⁺ dysregulation and subsequently inhibits ROS overproduction-mediated mitochondrial dysfunction. Transcriptomic analysis confirmed that mouse double minute 2 homolog (MDM2) may acts as a downstream target of activated SIRT1 in regulating MAMs formation and thereby protecting against the development of NAFLD. Taken together, this reseach revealed that SIRT1 activation inhibits the aberrant formation of MAMs caused by excessive calorie intake. This effect is linked to the suppression of MDM2 expression and disruption of its interaction of MDM2 with resident MAMs Ca2 + channels by SIRT1, ultimately alleviating mitochondrial Ca2⁺ overload induced mitochondria oxidative stress.

Keywords:  Mitochondria-associated membranes; Mouse double minute 2 homolog; Nonalcoholic fatty liver disease; SIRT1 signal

DOI:  https://doi.org/10.1186/s12964-025-02251-7
Front Pharmacol. 2025 ;16 1692250

Anticancer activity of MDM2 inhibition in 2D and bioprinted 3D retinoblastoma cell models.

Francesca Bompan, Giada Lodi, Rebecca Foschi, Anna Dipinto, Lucia Carmela Cosenza, Fabio Casciano, Paolo Severi, Anna Sanvido, Lorenzo Caruso, Luisa Giari, Giorgio Zauli, Rebecca Voltan, Arianna Romani.

  Retinoblastoma is the most common childhood tumor affecting the retina. Pharmacological resistance or delayed intervention leads to the loss of vision. Therefore, novel therapeutic strategies need to be assessed in preclinical models that mimic the in vivo tumor. This project aims to investigate the anticancer activity of the MDM2 inhibitor, nutlin-3a, in the treatment of retinoblastoma using both conventional 2D in vitro models and more-realistic 3D-bioprinted models. Unlike many cancers, retinoblastoma presents a p53 wild-type phenotype, making the p53 pathway a promising target for pharmacological treatment via MDM2 inhibitors. Initially, nutlin-3a was tested on Y79 and Weri-Rb1 retinoblastoma 2D cell line cultures. A significant, concentration-dependent reduction in cell viability was observed as early as 24 h, associated with cell cycle blockade in both S and G2/M phases, assessed through cytofluorimetric analysis. Activation of the p53 pathway was observed by Western blotting. Second, the same cell lines were used to generate innovative 3D-bioprinted models using 2% alginate and 5% gelatin bioinks. The 3D structures were treated with nutlin-3a for 72 h and assessed for viability using MTT or fixed and embedded in paraffin for histological and immunohistochemical investigation. Hematoxylin and eosin staining of non-treated 3D structures evidenced an architecture similar to the primary tumor rosette formation. Interestingly, nutlin-3a treatment significantly reduced the dimension of rosettes in both 3D models; additionally, it reduced the number of rosettes in the Y79 3D model. These data were supported by a significant reduction in proliferation and a decrease in Ki-67 expression. Our 3D models closely resemble retinoblastoma tumor tissue and can serve as a platform to assess innovative drugs or implement the promising results on the use of MDM2 inhibitors for retinoblastoma treatment.

Keywords:  Weri-Rb1; Y79; bioprinted model; nutlin-3a; retinoblastoma

DOI:  https://doi.org/10.3389/fphar.2025.1692250
Dig Dis Sci. 2025 Nov 29.

Helicobacter pylori Lipopolysaccharide Upregulates MDM2 via the TLR4/MAPK/AP-1 Pathway to Promote Gastric Cancer Progression.

Yuqin Li, Lin Xu, Xiaolan Lu, Baiqing Fu, Qiuyu Jiang, Wujun Xiong, Wenqing Tang, Dejun Wu.

   BACKGROUND: The lipopolysaccharide (LPS) of Helicobacter pylori (HP) is a critical virulence factor in gastric cancer development. As a toxic component of the HP cytoderm, HP LPS causes persistent inflammatory injury to the gastric mucosa. Although HP lipopolysaccharide exhibits weaker endotoxic activity, it still promotes gastric cancer progression by inducing chronic inflammation and enhancing cellular proliferation. However, the specific signaling pathways involved are not fully understood.
METHODS: GES-1, HGC-27, and MKN-45 cells were treated with LPS from HP and E. coli. Western blotting and a luciferase reporter assay were used to analyze MDM2 expression and transcriptional activity. Cell proliferation, migration, and invasion were evaluated through colony formation, scratch wound healing, and transwell assays. Immunohistochemistry was used to examine MDM2 and p53 expression, while immunofluorescence detected regulatory T cells. Gastric cancer mouse models were also used to confirm MDM2's role in gastric cancer.
RESULTS: HP infection resulted in elevated MDM2 levels in gastric precancerous lesions and cancers. HP LPS enhances MDM2 expression in GC cells. This effect is mediated through TLR4/MAPK/AP-1, which promotes the proliferation and invasion of gastric cancer cells. In addition, MDM2 participated in Tregs infiltration and promoted the maintenance of an immunosuppressive tumor microenvironment in gastric cancer.
CONCLUSIONS: HP LPS enhances MDM2 expression in GC cells through the TLR4/MAPK/AP-1 pathway. MDM2 mediates the protumor effects of HP LPS by promoting tumor cell proliferation and regulating Treg-mediated immune suppression. Our study deepens the understanding of gastric cancer progression and identifies MDM2 as an effective therapeutic target.

Keywords:  Gastric cancer; Lipopolysaccharide; MDM2; Tumorigenesis

DOI:  https://doi.org/10.1007/s10620-025-09576-w
Medicina (Kaunas). 2025 Oct 30. pii: 1948. [Epub ahead of print]61(11):

The Association and Significance of MDM2 and NF-κB Protein Expression in Multiple Myeloma.

Marija Stanić Damić, Aron Grubešić, Zinaida Perić, Nives Jonjić, Irena Seili-Bekafigo, Goran Hauser, Nina Jajaš, Toni Valković.

  Background and Objectives: This pilot study examines the expression of MDM2 and NF-κB proteins in CD138-positive plasma cells in patients with multiple myeloma treated with bortezomib-based therapy, exploring their possible interplay and correlations with clinical and selected prognostic factors. Materials and Methods: We analyzed MDM2 and NF-κB protein expression via double immunohistochemical staining of bone marrow trephine biopsies obtained at diagnosis and after bortezomib-based therapy. Statistical analyses were performed to assess the significance of changes in protein expression before and after therapy and their association with clinical and prognostic parameters. Results: Key findings revealed a positive correlation between MDM2 and NF-κB, as well as a significant decrease in their expression following therapy. Decreased NF-κB expression seems to be an independent prognostic factor for improved renal function. Conclusions: The results demonstrated for the first time the in vivo protein expression of MDM2 in the bone marrow of patients with multiple myeloma, as well as the possible effect of bortezomib on the expression of this protein in the microenvironment of multiple myeloma.

Keywords:  MDM2; NF-κB; biomarker; bortezomib; multiple myeloma; protein expression; renal impairment

DOI:  https://doi.org/10.3390/medicina61111948
Asian Pac J Cancer Prev. 2025 Nov 01. pii: 91936. [Epub ahead of print]26(11): 4097-4101

Genetic Polymorphism of MDM2 Gene Associates with Breast Cancer Incidence in the Lower Northern Thailand.

Metawee Srikummool, Maturos Nakmoo, Surasak Ditha.

   OBJECTIVE: Breast cancer remains the most prevalence among women worldwide, including those in lower northern Thailand. This study aimed to investigate the association between selected genetic polymorphisms and breast cancer incidence in this regional population.
METHODS: DNA samples were obtained from 184 breast cancer patients and 176 healthy controls. Twelve biallelic genetic markers across nine genes were genotyped using PCR-RFLP, TaqMan probe, and KASP-PCR genotyping assays. Allelic frequencies were calculated for each marker, and odds ratios (OR) was used to assess the association between genetic polymorphism and breast cancer risk.
RESULT: Among the loci studied, only the deletion allele of MDM2 rs150550023 showed a significant association with breast cancer risk in the lower northern Thai population (OR = 1.44; 95 % CI = 1.033 - 2.008, p = 0.016). This allele was found at a high frequency (23.3%).
CONCLUSION: These findings suggest that the deletion allele of MDM2 rs150550023 may serve as a potential genetic marker for breast cancer susceptibility in the lower norther Thai population.

Keywords:  Genetic polymorphism; MDM2 gene; breast cancer; lower norther Thailand

DOI:  https://doi.org/10.31557/APJCP.2025.26.11.4097
BMC Cancer. 2025 Nov 26.

MDM2-amplified esophageal adenocarcinomas exhibit an activated metabolic and immunosuppressive phenotype with multiple potential therapeutic targets.

Karl Knipper, Christiane J Bruns, Felix C Popp, Thomas Schmidt, Bastian Grothey, Alexander Quaas, Su Ir Lyu.

   BACKGROUND: A complete response following neoadjuvant therapy occurs only in a fraction of patients with esophageal adenocarcinoma (EAC). Further targeted treatment options are needed to improve treatment response and patient survival. Mouse double minute 2 homolog (MDM2) is a known oncogene. It is currently under investigation as a potential therapeutic target. However, initial findings have not been groundbreaking. Therefore, this study aimed to identify further potential therapeutic targets in the subtype of MDM2-amplified EAC.
METHODS: We screened 656 patients with esophageal adenocarcinoma for their MDM2-amplification status using Fluorescence in situ Hybridization. 57 tumors (8.7%) were MDM2-amplified. The proteome of 35 MDM2-amplified and 37 non-amplified tumors was analyzed using mass spectrometry.
RESULTS: The comparison of MDM2-amplified and non-amplified tumors revealed various differently expressed proteins and pathways. Hornerin and Bystin were significantly downregulated. Whereas Choline transporter-like protein 2 and Contactin 1 were upregulated in MDM2-amplified EAC. Enrichment analyses revealed that MDM2-amplified EAC showed a more pronounced immunosuppressive phenotype. Furthermore, distinct metabolic pathways like propanoate and tryptophan metabolism were upregulated.
CONCLUSIONS: Summarizing, we described numerous potential therapeutic targets, suggesting patients with MDM2-amplified tumors could potentially benefit from, exemplary, Mitogen-activated protein kinase kinase inhibitors or tryptophan metabolism inhibitors in new combinational treatment regimens. Future mechanistic studies are needed to validate these findings.

Keywords:  Amplification; Esophageal adenocarcinoma; MDM2; Personalized medicine; Prognosis; Proteomics

DOI:  https://doi.org/10.1186/s12885-025-15367-3
Pathol Res Pract. 2025 Nov 17. pii: S0344-0338(25)00491-1. [Epub ahead of print]277 156298

EGCG inhibits hepatic stellate cell activity and liver fibrosis by targeting the MDM2/MUC5AC-mediated TGF-β1/Smad signaling pathway.

Longbao Yang, Fenrong Chen, Xiong Li, Xiaoke Sun, Hong Li, Haitao Shi, Gang Zhao.

   OBJECTIVE: To investigate the intervention effect of epigallocatechin gallate (EGCG) on liver fibrosis and its underlying molecular mechanisms.
METHODS: A mouse model of liver fibrosis induced by a high-fat diet was established, with groups divided into normal control, high-fat diet (HF) group, and HF + EGCG groups (low, medium, and high doses). The therapeutic effect of EGCG on liver fibrosis was evaluated by liver pathological scoring, detection of serum biochemical indicators, analysis of fibrotic markers, and Western blot for fibrotic protein expression. LX-2 cells were cultured in vitro and activated by TGF-β1. Molecular biology experiments (RT-qPCR, Western blot, immunofluorescence, co-immunoprecipitation, etc.) were used to explore the effects of EGCG on LX-2 cell activation, proliferation, migration, and its regulation of the TGF-β/Smad signaling pathway. Ubiquitination assays, molecular docking, and enzyme inhibitor interventions were performed to clarify the regulatory mechanism of EGCG on MUC5AC stability and its interaction with MDM2. Gene silencing/overexpression techniques were used to verify the critical role of the MDM2/MUC5AC axis in EGCG's anti-fibrotic effect.
RESULTS: In vivo experiments showed that EGCG dose-dependently improved liver histological damage in high-fat diet-fed mice, reduced serum levels of ALT, AST, and TBil, increased albumin and prothrombin time, decreased the expression of fibrotic markers such as hyaluronic acid (HA) and laminin (LN), and inhibited the expression of fibrotic proteins including α-SMA and collagen I. In vitro experiments confirmed that EGCG reduced activation, proliferation, and migration of LX-2 cells by inhibiting the TGF-β1/Smad signaling pathway (downregulating Smad2/3 phosphorylation and upregulating Smad7). Mechanistically, EGCG targeted and bound to MDM2, inhibiting MDM2-mediated ubiquitination and degradation of MUC5AC, thereby increasing MUC5AC protein stability. MUC5AC directly interacted with TGF-β1, further inhibiting the activation of the TGF-β1/Smad pathway. Additionally, overexpression of MDM2 reversed the upregulation of MUC5AC and the anti-fibrotic effect of EGCG, while supplementation of MUC5AC restored the intervention effect of EGCG, confirming that EGCG exerts its function through the MDM2/MUC5AC axis.
CONCLUSION: EGCG targets MDM2 to prevent MUC5AC from ubiquitination and degradation. The upregulated MUC5AC binds to TGF-β1 and inhibits the TGF-β1/Smad signaling pathway, thereby suppressing hepatic stellate cell activation and liver fibrosis progression. This study provides new potential targets and experimental basis for the prevention and treatment of liver fibrosis.

Keywords:  EGCG; Liver fibrosis; MDM2; MUC5AC; TGF-β1/Smad signaling pathway

DOI:  https://doi.org/10.1016/j.prp.2025.156298
Cell Rep Med. 2025 Nov 26. pii: S2666-3791(25)00540-3. [Epub ahead of print] 102467

A triple-action PROTAC for wild-type p53 cancer therapy.

Gregory H Bird, Utsarga Adhikary, Michael J Schmidt, Marina Godes, Bethany Tesar, Christina M Camara, Joao A Paulo, Julia F Vidlak, Thomas M DeAngelo, Marilyn Marquez, Prafulla Gokhale, Ruitong Li, Shannan J Ho Sui, Michael D Cameron, Steven P Gygi, Loren D Walensky.

  Despite the central role of p53 suppression in cancer pathogenesis, the promise of therapeutic p53 reactivation remains unrealized, with targeted and combination chemotherapies limited by efficacy, toxicity, and delivery. To overcome these challenges, we introduce a triple-action proteolysis targeting chimera (TAPTAC) that simultaneously targets three oncogenic mechanisms to reactivate apoptosis. TAPTAC1 diverts HDM2 from degrading p53 to eliminating oncogenic targets such as BET proteins, while also blocking HDMX-mediated sequestration, thereby maximizing p53 reactivation in concert with cancer protein degradation. TAPTAC1 outperforms combination treatments and PROTACs that target HDM2 and BET proteins, but not HDMX, and is broadly effective in wild-type (WT) p53 cancers, including mouse models of osteosarcoma and leukemia. Importantly, TAPTAC1 leverages cancer dependency on HDM2 to enhance selectivity and mitigate toxicity. With WT p53 retained in 90% of pediatric and 50% of adult cancers, TAPTACs provide a therapeutic platform for addressing key limitations of prior anti-cancer strategies.

Keywords:  Apoptosis; BET inhibitor; BRD4; Cancer; HDM2; HDMX; PROTAC; TAPTAC; degrader; p53; stapled p53 peptide; therapeutics

DOI:  https://doi.org/10.1016/j.xcrm.2025.102467