PLAGL1 overexpression exacerbates type 1 diabetes by inducing β-cell apoptosis via oxidative stress-dependent dual...

Type 1 diabetes mellitus (T1DM) arises from autoimmune destruction of pancreatic β-cells. Pleomorphic adenoma gene-like 1 (PLAGL1) overexpression has been linked to β-cell apoptosis, but molecular mechanisms remain incompletely understood. This study explored whether PLAGL1 exacerbates T1DM by promoting oxidative stress-induced DNA damage and activating the cGAS/STING inflammatory pathway.

The mouse β-cell line NIT-1 was transfected with PLAGL1 overexpression plasmids or specific siRNA. Mitochondrial and nuclear DNA damage was assessed through comet assays, 8-OHdG ELISA, and Western blot analysis of key DNA repair proteins, including XRCC1, OGG1, and PARP1. Oxidative stress was evaluated by measuring superoxide dismutase (SOD) activity and the glutathione redox state (GSH/GSSG ratio), while apoptosis was examined via expression levels of BCL2, BAX, and cleaved Caspase-3. To investigate pathway involvement, pharmacological inhibitors-RU.521 (targeting cGAS) and H-151 (targeting STING)-were applied. In NOD mice, PLAGL1 overexpression was combined with cGAS/STING inhibition; glucose tolerance was subsequently evaluated, and pancreatic tissue was subjected to histopathological examination.

Overexpression of PLAGL1 triggered substantial mitochondrial and nuclear DNA damage, which was accompanied by elevated oxidative stress and compromised DNA repair. Consequently, cytoplasmic DNA accumulated, leading to activation of the cGAS/STING pathway and subsequent β-cell apoptosis and functional decline. Treatment with the cGAS inhibitor RU-521 or the STING inhibitor H-151 markedly attenuated apoptosis and restored insulin secretion in PLAGL1-overexpressing NIT-1 cells. In NOD mice, PLAGL1 overexpression accelerated diabetes progression, whereas inhibition of the cGAS/STING axis preserved β-cell mass, improved glucose homeostasis, and sustained insulin output. Histological evaluation further confirmed that inhibition of this signaling pathway helped maintain normal islet architecture.

Our findings demonstrated that PLAGL1 exacerbates β-cell loss in type 1 diabetes by driving oxidative DNA damage and activating the cGAS/STING signaling cascade. Therapeutic intervention targeting this axis may therefore represent a promising strategy to protect β-cells and attenuate disease progression.