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. 2025 Mar;83(1):783-792.
doi: 10.1007/s12013-024-01510-7. Epub 2024 Sep 8.

HMGA1 Regulates IRS2 to Promote Inflammatory Responses and Oxidative Stress Injury in MPP+-Induced cells

Dongxun Xu  1 , Wenhui Fan  1 , Bing Fu  2 , Hongxia Nie  3
Affiliations

HMGA1 Regulates IRS2 to Promote Inflammatory Responses and Oxidative Stress Injury in MPP+-Induced cells

Dongxun Xu et al. Cell Biochem Biophys. 2025 Mar.

Abstract

Parkinson's disease (PD) is a prevalent neurodegenerative disorder for which novel treatment approaches are continuously sought. This study investigates the role of high-mobility group A1 (HMGA1) in modulating inflammatory responses and oxidative stress injury in PD. We utilized the murine dopaminergic neuronal cell line MN9D, treating cells with 1-methyl-4-phenylpyridinium ion (MPP+) to mimic PD conditions. The expression levels of HMGA1 and insulin receptor substrate 2 (IRS2) were measured using quantitative polymerase chain reaction and Western blot assay. Cell damage was assessed with cell counting kit-8 and lactate dehydrogenase assays. Inflammatory response and oxidative stress were evaluated by quantifying interleukin (IL)-1β, IL-6, tumor necrosis factor-α, reactive oxygen species, superoxide dismutase, and malondialdehyde (MDA) levels using enzyme-linked immunosorbent assay and commercial kits. The binding interaction between HMGA1 and IRS2 was analyzed using chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assays. Our findings revealed that MPP+ treatment increased the expression of HMGA1 and IRS2. Downregulation of HMGA1 enhanced cell viability, reduced inflammation, and mitigated oxidative stress in MPP+-induced cells. Further investigation demonstrated that HMGA1 bounded to the IRS2 promoter, enhancing IRS2 expression. Overexpression of IRS2 counteracted the protective effects of HMGA1 downregulation. In conclusion, HMGA1 exacerbates MPP+-induced cell damage by activating IRS2 transcription, which in turn heightens inflammation and oxidative stress. These findings suggest that targeting HMGA1 could be a potential therapeutic strategy for PD.

Keywords: HMGA1; IRS2; MPP+; Oxidative stress; Parkinson’s disease.

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Conflict of interest statement

Compliance with Ethical Standards. Conflict of interest: The authors declare no competing interests.

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