小檗碱通过丁酸钠介导的HDAC1/GPX4轴抑制铁死亡缓解糖尿病肾病

Abstract

Berberine demonstrates protective effects against diabetic kidney disease (DKD), yet its underlying mechanisms remain incompletely understood. This study investigated whether berberine alleviates DKD through modulation of the gut microbiota and the sodium butyrate-mediated HDAC1/GPX4 axis (Histone deacetylase 1 / glutathione peroxidase 4). In diabetic (db/db) mice, berberine treatment significantly ameliorated renal injury, reduced proteinuria and serum creatinine, increased the abundance of the butyrate producing bacterium Lachnospiraceae and plasma butyrate levels, while downregulating renal HDAC1 and upregulating GPX4 expression. In high glucose (HG) stimulated human renal glomerular endothelial cells (HRGECs), sodium butyrate enhanced cell viability, improved tube formation, and suppressed lipid peroxidation, effects counteracted by the ferroptosis inducer RSL3. Sodium butyrate inhibited HG-induced HDAC1 expression, increased H3K9 acetylation, and enriched H3K9ac binding to the GPX4 promoter. Overexpression of HDAC1 attenuated sodium butyrate's protective effects against HG-induced injury and ferroptosis. In conclusion, berberine attenuates DKD by increasing sodium butyrate, which modulates the HDAC1/GPX4 axis to inhibit ferroptosis in glomerular endothelial cells, providing a novel mechanistic insight and potential therapeutic strategy.