Discovery of bakuchiol as an AIM2 inflammasome activator and cause of hepatotoxicity.

ETHNOPHARMACOLOGICAL RELEVANCE

Psoralea corylifolia (P. corylifolia Linn.) is a traditional Chinese medicinal plant that exhibits significant aphrodisiac, diuretic, and anti-rheumatic effects. However, it has been reported to cause hepatic injury, but the precise mechanisms remain unclear.

AIM OF THE STUDY

To evaluate the safety and risk of P. corylifolia and to elucidate the underlying mechanisms of drug-induced liver injury.

MATERIALS AND METHODS

Western blotting, enzyme-linked immunosorbent assay (ELISA), immunofluorescence, quantitative polymerase chain reaction (Q-PCR), and flow cytometry were used to explore the effect of bakuchiol (Bak), one of the most abundant and biologically active components of P. corylifolia, on the AIM2 inflammasome activation and the underlying mechanism. Furthermore, we used the lipopolysaccharides (LPS)-induced drug-induced liver injury (DILI) susceptible mice model to study the Bak-mediated hepatotoxicity.

RESULTS

Bak induced the maturation of caspase-1 P20, and significantly increased the expression of IL-1β and TNF-α (P < 0.0001) compared with the control group. Moreover, compared to the Bak group, knockdown of AIM2 inhibited Bak-induced caspase-1 maturation and significantly decreased the production of IL-1β and TNF-α, but knockout of NLRP3 had no effect. Mechanistically, Bak-induced AIM2 inflammasome activation is involved in mitochondrial damage, mitochondrial DNA (mtDNA) release, and subsequent recognition of cytosolic mtDNA. Our in vivo data showed that co-exposure to LPS and non-hepatotoxic doses of Bak significantly increased the levels of ALT, AST, IL-1β, TNF-α, and IL-18, indicating that Bak can induce severe liver inflammation (P < 0.005).

CONCLUSIONS

The result shows that Bak activates the AIM2 inflammasome by inducing mitochondrial damage to release mtDNA, and subsequently binds to the AIM2 receptor, indicating that Bak may be a risk factor for P. corylifolia-induced hepatic injury.