α-Ketoglutarate Alleviates the Pathogenesis of Systemic Lupus Erythematosus via Reducing Oxidative Stress and Attenuating Excessive Immune Response

Background: Systemic lupus erythematosus (SLE) is a systemic autoimmune disease driven by dysregulated immune activation, with heterogeneous clinical manifestations and multi-organ injury. α-ketoglutarate (AKG) is a key intermediate metabolite of the tricarboxylic-acid cycle (TCA), participating in various physiological processes, including energy metabolism and immune regulation. Methods: In this study, 8-week-old female BALB/c mice were injected with pristane to establish an SLE mouse model. Using this model, we explored the therapeutic function and underlying mechanism of AKG intervention on SLE. Results: AKG administration significantly reduced serum antinuclear antibody (ANA) levels and alleviated renal injuries and biochemical improvement in SLE mice. Furthermore, it effectively maintained glomerular integrity and decreased the serum levels of biochemical enzymes and indices. Meanwhile, oxidative stress was ameliorated associated with the capacity of endogenous antioxidant enzymes and reducing the level of malondialdehyde (MDA). Most importantly, AKG upregulated the transcriptional levels of genes related to mitochondrial respiratory-chain complex, and increasing the production of adenosine triphosphate (ATP) in kidney tissues. Moreover, AKG administration regulated the proportion of spleen immune cells, and improved inflammation by decreasing the Interferon-stimulated genes (ISGs) expression levels, suppressing the liberation of inflammatory cytokines, ultimately alleviating SLE-associated damage. Conclusions: In summary, AKG protects against SLE through multi-targeted pathways, including suppressing oxidative stress, improving mitochondrial biogenesis-related factors, modulating immune-cell profiles, and dampening inflammatory response. These findings indicate that AKG has the effect of improving SLE.