Cardamonin Commands the Colonic Metabolite Columbianetin Acetate to Compete Against LPS in Binding HMGB1 in the Kidney, Preventing Lipopolysaccharide‐Induced Renal Tubular Pyroptosis

ABSTRACT Sepsis‐associated acute kidney injury (SA‐AKI) results in high mortality due to the lack of effective interventions. The current study reports the protective effect of cardamonin (CAD), a member of the chalcone family, against SA‐AKI using a lipopolysaccharide (LPS)‐stimulated mouse model. CAD was administered by gavage to the mice for 1 week prior to the intraperitoneal injection of LPS, showing a dramatic prevention of renal dysfunction and pathological damage, as well as renal inflammation, oxidative stress, and tubular pyroptosis. Surprisingly, CAD was undetectable in the serum but was significantly enriched in the colon. Metabolomic analysis of the colonic content identified that columbianetin acetate (CA) was drastically increased by CAD. Further measurements confirmed the increase of CA levels in both the colonic content and serum. One‐week oral delivery of CA produced a remarkable preventive effect on LPS‐induced AKI in mice. Combination of network pharmacology, molecular docking, and surface plasmon resonance identified high mobility group box 1 (HMGB1) as the primary target of CA. Further investigation found that CA competed with LPS to bind HMGB1, reducing cellular uptake of LPS, stabilizing lysosomes, and mitigating renal tubular cell pyroptosis. The present study may provide CAD and CA as effective nutritional approaches for SA‐AKI intervention.