This study aimed to investigate whether the protective effect of 6-shogaol on aging-induced renal injury is associated with autophagy mediated by the PI3K/AKT/FoxO3 signaling pathway. The aging mouse model was established by intraperitoneal injection of D-galactose (D-gal), followed by intragastric administration of 6-shogaol at low, medium and high doses (5, 10, 20 mg/kg body weight). We measured serum creatinine (CRE) and blood urea nitrogen(BUN) levels. We examined renal histopathology and aging status using hematoxylin-eosin (H&E) staining, Masson's trichrome staining, and β-galactosidase staining. We determined superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and malondialdehyde (MDA) levels in renal tissue. The mRNA expression levels of Beclin1, LC3, Cdkn1a, PI3K, AKT, and FoxO3 were quantified by quantitative real-time PCR (qRT-PCR). We assessed the expression of autophagy marker proteins Beclin1 and LC3B using Immunohistochemistry(IHC). We also evaluated PI3K/AKT/FoxO3 pathway-related protein expression and phosphorylation status. Compared with the control group, the D-gal group displayed reduced organ coefficients(P<0.01), increased serum BUN and CRE levels(P<0.05), severe renal histopathological injury and collagen deposition, accelerated aging phenotypes, decreased SOD and GSH-Px activities(P＞0.05), elevated MDA content(P<0.05), together with upregulated mRNA levels of Beclin1, LC3, Cdkn1a, AKT and FoxO3 and enhanced protein expression of the autophagy markers Beclin1 and LC3B(P<0.05), downregulated p-AKT/AKT(P<0.05). When compared with the D-gal model group, 6-shogaol intervention decreased serum BUN and CRE levels in a dose-dependent manner, with the medium-dose group showing the optimal therapeutic effect(P<0.05). Meanwhile, 6-shogaol ameliorated renal histopathological damage, elevated SOD and GSH-Px activities, and lowered MDA content(P<0.01). Furthermore, it downregulated the mRNA levels of LC3, Cdkn1a, PI3K and FoxO3 as well as the protein expression of autophagy-related markers Beclin1 and LC3B(P<0.05), while concurrently increasing the phosphorylation of PI3K/AKT/FoxO3 pathway proteins(P<0.05). Collectively, these findings demonstrate that 6-shogaol can alleviate aging-induced renal injury, and its renoprotective mechanism may involve the inhibition of excessive autophagy via modulating the PI3K/AKT/FoxO3 signaling pathway.

Yuehan Zhu, Ziqi Chen, Jiansheng Cai, Tingyu Mai, Chaofan Xie, Bin Wang, You Li. 6-Shogaol Attenuates Renal Aging Induced by D-galactose via Inhibiting PI3K/AKT/FoxO3 Signaling-mediated Autophagy. Frontiers in Medical Science Research (2026), Vol. 8, Issue 5: 12-22. https://doi.org/10.25236/FMSR.2026.080502.

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