Work

ZNF503-AS-Pep1 mitigates neuroinflammation and oxidative stress via HMGA2 in a microglia-mediated neuroinflammatory cell model

Year: 2026

Type: article

Abstract: Neuroinflammation and oxidative stress are critical pathological drivers in various neurological and neuropsychiatric disorders, with IL6 and reactive oxygen species (ROS) as key factors. This study investigated the lncRNA-derived peptide ZNF503-AS-Pep1’s role in modulating these pathways in cell model in vitro and its molecular mechanism. In this study, HMC3 cells were used to construct an LPS-induced inflammatory cell model to simulate a neuroinflammatory condition. Oxidative stress was evaluated by measuring ROS, MDA, and SOD levels. Dual-luciferase reporter assays assessed the impact on the transcriptional activity of IL6 promoter. Enzyme-linked immunosorbent assay (ELISA) and RT-qPCR were used to measure IL6 level. DNA pull-down combined with MS was utilized to identify proteins interacting with the IL6 promoter region. Co-immunoprecipitation (Co-IP) and Venn diagram analyses were employed to further determine key intermediate regulatory proteins between ZNF503-AS-Pep1 and IL6. Chromatin immunoprecipitation (ChIP-PCR and ChIP-qPCR) and computational structural modeling were performed to elucidate protein-DNA and peptide-protein interactions, while antisense oligonucleotides (ASOs) were utilized for loss-of-function validation. The results showed that ZNF503-AS-Pep1 markedly reduced IL6 transcription and secretion, effectively mitigating the pro-inflammatory state and oxidative damage in LPS-stimulated HMC3 cells, whereas knockdown of endogenous ZNF503-AS-Pep1 exacerbated these pathological phenotypes. HMGA2 was identified as a key intermediary protein connecting ZNF503-AS-Pep1 and IL6, with ZNF503-AS-Pep1 inhibiting HMGA2’s enhancement of IL6 transcription by physically hindering HMGA2 occupancy at the IL6 promoter. Additionally, ZNF503-AS-Pep1 alleviated HMGA2-induced oxidative damage, as evidenced by reduced ROS and MDA levels and increased SOD activity. In conclusion, ZNF503-AS-Pep1 exerted a protective role in reducing IL6 transcription and oxidative damage by modulating HMGA2 in an inflammatory cell model. These findings suggested that ZNF503-AS-Pep1 could serve as a promising therapeutic candidate for mitigating neuroinflammation and oxidative stress in neuroinflammatory disorders, including schizophrenia.

Source: Amino Acids

DOI: 10.1007/s00726-026-03565-7

Authors: Yatang Chen, Yilin Liu, Lei Yu, Yong Zeng, Yongquan Lu

Institutions: Chongqing University, Chongqing Emergency Medical Center, Kunming Medical University

Language: English

Topic: Neuroinflammation and Neurodegeneration Mechanisms

Subfield: Neurology

Field: Neuroscience

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $3,590