Ginsenoside Rg1 protects against radiation-induced hippocampal injury via downregulation of lncRNA ENPP2-AS to alleviate oxidative stress and inflammation

Objective To evaluate whether ginsenoside Rg1 protects against cranial irradiation-induced hippocampal injury and cognitive decline, and to explore the underlying lncRNA-mediated mechanisms via transcriptomic analysis. Methods Sixty-four male C57BL/6J mice were divided into four groups (Control, IR, IR + Rg1, and Rg1; n = 16). Mice in the IR + Rg1 and Rg1 groups received Rg1 (20 mg/kg, i.p.) for 30 d, after which the IR and IR + Rg1 groups were exposed to 5 Gy whole-brain X-ray irradiation. Hippocampal tissues were collected at 30 and 90 d post-irradiation. Morris water maze was used to assess spatial learning and memory; immunofluorescence staining to evaluate hippocampal neurogenesis; and ELISA to measure inflammatory cytokines. In vitro , HT22 cells were divided into six groups (control, IR, IR + Rg1 at 20, 40, or 80 μg/mL, and IR + SB 216763), with irradiated groups exposed to 5 Gy X-ray. siRNA silencing was used to examine the function of candidate lncRNAs in HT22 cells. Results Rg1 improved spatial memory at 90 d, with reduced escape latency (IR: 11.44 ± 0.86 vs. IR + Rg1: 6.49 ± 0.88, t = 4.40, P < 0.05). Rg1 enhanced neurogenesis ( BrdU+/DCX+ cells: IR: 8.00 ± 2.08 vs. IR + Rg1: 40.30 ± 4.81, t = 6.34, P < 0.05), and reduced IL-1β (IR: 50.43 ± 1.19 vs. IR + Rg1: 33.35 ± 0.57, t = 13.70, P < 0.05). Transcriptomic analysis identified ENPP2-AS as a novel radiation-responsive lncRNA downregulated by Rg1; its knockdown reduced downstream targets (Enpp2 and Ttr) and recapitulated the antioxidant and anti-inflammatory effects in HT22 cells. Conclusions Ginsenoside Rg1 alleviates radiation-induced hippocampal injury and cognitive impairment by downregulating ENPP2-AS to mitigate oxidative stress and inflammation.