Α-Ketoglutarate ameliorates appendicitis by modulating Gln metabolism and inhibiting NF - κB signaling pathway

Acute appendicitis, a prevalent surgical emergency, is characterized by dysregulated immune responses and metabolic disturbances. Current therapeutic strategies, including surgical intervention and antibiotic therapy, remain limited by complications and recurrence risks. This study investigates the role of Glutamine (Gln) metabolism and its downstream metabolite α-Ketoglutarate (α-KG) in modulating inflammation and intestinal barrier dysfunction during appendicitis.

Transcriptomic profiling of human appendiceal tissues and murine cecal ligation and puncture (CLP) models were employed. Clinical specimens from acute appendicitis patients and murine sepsis models were analyzed via RNA sequencing, RT-qPCR, immunofluorescence, and biochemical assays. The therapeutic effects of exogenous α-KG supplementation were evaluated through survival analysis, cytokine profiling, and NF-κB pathway modulation.

Inflamed appendiceal tissues exhibited marked downregulation of Gln catabolic genes (GLS1, GLUD1) and reduced α-KG levels, correlating with NF-κB hyperactivation and cytokine storms. Murine CLP models confirmed impaired Gln-α-KG axis activity, exacerbating systemic inflammation. Exogenous α-KG supplementation suppressed p65 phosphorylation, stabilized IκBα, and attenuated pro-inflammatory cytokines (IL-6, TNF-α), significantly improving survival rates. Combined α-KG and antibiotic therapy demonstrated synergistic efficacy, while Gln alone showed limited benefits.

Dysfunctional Gln metabolism drives appendicitis pathogenesis through NF-κB-mediated inflammation. In our preclinical models, α-KG demonstrated potent therapeutic effects, alleviating disease progression via both metabolic and anti-inflammatory mechanisms. These results from animal studies and human tissue analysis highlight α-KG as a potential adjunctive therapy for acute appendicitis, laying the groundwork for further clinical exploration.