Apabetalone, a BET protein inhibitor, inhibits kidney damage in diabetes by preventing pyroptosis via modulating the P300/H3K27ac/PLK1 axis

Many inflammatory disorders, including diabetic kidney disease (DKD), are linked to pyroptosis—a form of inflammation-driven cell death. This study aimed to evaluate the impact of apabetalone, an inhibitor targeting BRD4, a bromodomain and extra-terminal (BET) protein that interacts with bromodomain 2, on kidney damage in DKD. Both pharmacological and genetic methods were used to assess apabetalone’s effects on pyroptosis in db/db mice and human tubular epithelial cells (HK-2).

The results showed that BRD4 levels were elevated in HK-2 cells exposed to high glucose and in db/db mice. Altering BRD4 levels influenced the production of inflammatory cytokines and pyroptosis through the activation of the NLRP3 inflammasome in both models. Apabetalone effectively mitigated these processes by inhibiting BRD4. Additionally, both apabetalone and BRD4 siRNA reduced PLK1 expression in high-glucose conditions by interfering with P300-dependent H3K27 acetylation at the PLK1 gene promoter, as confirmed by chromatin immunoprecipitation and immunoprecipitation assays.

In summary, apabetalone alleviates pyroptosis and fibrosis in DKD by regulating the BRD4/P300/H3K27ac/PLK1 axis, which drives NLRP3 inflammasome activation, inflammation, and fibrosis. These findings offer new insights into potential therapeutic approaches for DKD.