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Last update 08 May 2025

HMGA1

Last update 08 May 2025

Basic Info

Synonyms

high mobility group AT-hook 1, High mobility group AT-hook protein 1, High mobility group protein A1

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Introduction

HMG-I/Y bind preferentially to the minor groove of A+T rich regions in double-stranded DNA. It is suggested that these proteins could function in nucleosome phasing and in the 3'-end processing of mRNA transcripts. They are also involved in the transcription regulation of genes containing, or in close proximity to A+T-rich regions.

Drugs associated with HMGA1

NOX-A50

Target

HMGA1

Mechanism

HMGA1 inhibitors

Active Org.-

Originator Org.

TME Pharma NV

Active Indication-

Inactive Indication

Neoplasms

Drug Highest PhaseDiscontinued

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with HMGA1

100 Translational Medicine associated with HMGA1

0 Patents (Medical) associated with HMGA1

1,007

Literatures (Medical) associated with HMGA1

01 May 2025·eBioMedicine

HMGA1 deficiency: a pathogenic link between tau pathology and insulin resistance

Article

Author: Di Vito, Anna ; Brunetti, Francesco S ; Pierantoni, Giovanna M ; Nicoletti, Ferdinando ; Pascarella, Angelo ; Salatino, Alessandro ; Arcidiacono, Biagio ; Credendino, Sara C ; Aguglia, Umberto ; Huin, Vincent ; Brunetti, Antonio ; Greco, Adelaide ; Mirabelli, Maria ; Chiefari, Eusebio ; Morelli, Maurizio ; Fedele, Monica ; Foti, Daniela P

BACKGROUNDGrowing evidence links tau-related neurodegeneration with insulin resistance and type 2 diabetes (T2D), though the underlying mechanisms remain unclear. Our previous research identified HMGA1 as crucial for insulin receptor (INSR) expression, with defects in the HMGA1 gene associated with insulin resistance and T2D. Here, we explore HMGA1 deficiency as a potential contributor to tauopathies, such as Alzheimer's disease (AD), and its connection to insulin resistance.METHODSImmunoblot analyses, protein-DNA interaction studies, ChIP-qPCR, and reporter gene assays were conducted in human and mouse neuronal cell models. Tau immunohistochemistry, behavioural studies, and brain glucose metabolism were analysed in Hmga1-knockout mice. Additionally, a case-control study investigated the relationship between HMGA1 and tau pathology in patients with tauopathy, carrying or not the HMGA1 rs146052672 variant, known to reduce HMGA1 protein levels and increase the risk of insulin resistance and T2D.FINDINGSWe show that HMGA1 regulates tau protein expression primarily through the specific repression of MAPT gene transcription. In both human neuronal cells and primary mouse neurons, tau mRNA and protein levels were inversely correlated with HMGA1 expression. This inverse relationship was further confirmed in the brain of Hmga1-knockout mice, where tau was overexpressed, INSR was downregulated, and brain glucose uptake was impaired. Additionally, the rs146052672 variant was more common in patients with tauopathy (12/69, 17.4%) than in controls (10/200, 5.0%) (p = 0.001), and carriers of this variant exhibited more severe disease progression and poorer therapeutic outcomes.INTERPRETATIONThese findings suggest that HMGA1 deficiency may drive tau pathology, linking tauopathies to insulin resistance and providing new insights into the relationship between metabolic and neurodegenerative disorders. Furthermore, our observation that over 17% of individuals with tauopathy exhibit a deficit in HMGA1 protein production could have significant clinical implications, potentially guiding the development of therapeutic strategies targeting this specific defect.FUNDINGSee acknowledgements section.

01 Apr 2025·BJOG: An International Journal of Obstetrics & Gynaecology

Sigma‐1 Receptor‐Mediated High Mobility Group A1 Silencing Alleviates Endoplasmic Reticulum Stress‐Induced Ovarian Granulosa Cell Apoptosis: An In Vitro Cell Experimental Study

Article

Author: Zhang, Cuilian ; Jiang, Lile ; Yang, Shujun

ABSTRACTObjectiveTo investigate the role and underlying mechanism of sigma‐1 receptor (SigmaR1)/high mobility group A1 (HMGA1) in the pathogenesis of diminished ovarian reserve (DOR).DesignIn vitro cell experimental study.SettingThe Reproductive Medical Center, People's Hospital of Zhengzhou University.SampleSerum, follicular fluid (FF), ovarian granulosa cells (GCs) and KGN cells.MethodsSamples were collected from DOR patients. Endoplasmic reticulum (ER) stress was induced in the GCs using thapsigargin (TG). mRNA and protein levels were determined using reverse transcription‐quantitative polymerase chain reaction and western blotting. Cell apoptosis and viability were assessed using flow cytometry and cell counting kit‐8. Protein colocalization was detected via immunofluorescence. Molecular interactions were validated using co‐immunoprecipitation, luciferase reporter and chromatin immunoprecipitation assays.Main Outcome MeasuresCell viability, cell apoptosis, SigmaR1, HMGA1 and ER stress‐associated mRNA levels.ResultsSigmaR1 expression decreased while HMGA1 expression increased in the serum, FF and GC samples of DOR patients and TG‐treated GCs. TG induced ER stress and GC apoptosis; these effects were diminished by SigmaR1 overexpression or HMGA1 silencing. SigmaR1 expressed in the nuclear envelope forms a complex with gene repressor‐specific protein 3 (SP3) and histone deacetylase (HDAC)1/2/3; however, TG reduced SigmaR1 in GCs and blocked the complex formation. HMGA1, a transcriptional target of SP3, was negatively modulated by the SigmaR1/SP3 complex. HMGA1 overexpression abolished the protective effect of SigmaR1 on TG‐induced ER stress and GC apoptosis.ConclusionSigmaR1 formed a SmigaR1/SP3/HDAC complex to inhibit HMGA1 transcription, alleviating ER stress and GC apoptosis and providing new therapeutic targets for DOR.

01 Mar 2025·Translational Oncology

Multi-omic and machine learning analysis of mitochondrial RNA modification genes in lung adenocarcinoma for prognostic and therapeutic implications

Article

Author: Liu, Jiatao ; Wang, Wei ; Zhang, Xiao ; Lin, Haoran ; Yu, Yue ; Cao, Yaolin

Lung cancer remains the leading cause of cancer-related deaths, driven by complex pathogenesis and poor prognosis. Recognizing the pivotal role of mitochondrial RNA modifications (MRM) in cancer progression, this study aims to provide a comprehensive analysis of MRM-related genes and their clinical relevance in lung adenocarcinoma (LUAD). Integrating multi-omic datasets, we systematically explored the molecular features of MRM-related genes across various cancers and identified distinct expression patterns and prognostic associations. Single-cell analysis further reveals MRM-driven cell-cell interactions and pathway activation, particularly in cycling and epithelial cells. Using advanced machine learning techniques, we developed a novel prognostic signature-the Mitochondrial RNA Modification-related Signature (MRMS)-comprising nine genes: TXN, LDHA, HMGA1, SFTPB, KRT8, ALG3, S100A16, HSPD1, and ALDOA. The MRMS demonstrates superior predictive performance for LUAD survival compared to previously reported models. Our findings uniquely link MRMS to increased tumor mutational burden, genetic instability, and an immunosuppressive tumor microenvironment characterized by reduced immune cell infiltration and elevated tumor purity. Additionally, MRMS is associated with immunotherapy-related features, suggesting its potential in predicting treatment response. Experimental validation identified ALG3 as an oncogenic driver in LUAD, influencing tumor cell proliferation, migration, and invasion. In conclusion, this study establishes MRMS as a robust prognostic biomarker and highlights its dual role in shaping the tumor immune microenvironment and guiding therapeutic strategies. These findings provide novel insights into mitochondrial RNA modifications and their potential applications in personalized treatment for LUAD.

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HMGA1

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