BRD2-Mediated TGR5 Destabilization Impairs Fatty Acid Oxidation and Drives Tubular Ferroptosis in Diabetic Kidney Injury.
TL;DR
A BRD2-TGR5-FAO signaling axis is delineated as a central pathogenic driver of tubular lipotoxicity and ferroptosis in diabetic kidney injury, and BRD2 inhibition is position as a mechanistically grounded therapeutic strategy for diabetic kidney disease.
Abstract
Diabetic kidney injury is characterized by metabolic dysregulation, mitochondrial dysfunction, and tubular lipotoxicity; however, the molecular mechanisms integrating these pathological hallmarks remain incompletely elucidated. Here, we identify the epigenetic reader BRD2 as a pivotal regulator of renal tubular fatty acid oxidation (FAO) and ferroptosis. In streptozotocin-induced diabetic mice, BRD2 expression was progressively upregulated specifically in renal tubules, temporally coinciding with the onset and progression of tubular injury. Tubule-specific genetic ablation of Brd2 markedly attenuated diabetic nephropathy, as demonstrated by significant reductions in albuminuria, preservation of creatinine clearance, and amelioration of histopathological abnormalities including tubular atrophy, interstitial fibrosis, and lipid droplet accumulation. Mechanistically, BRD2 deficiency enhanced tubular FAO flux, reduced intracellular lipid accumulation, and suppressed ferroptosis, as evidenced by increased GPX4 and SLC7A11 protein levels, decreased ACSL4 expression, and diminished lipid peroxidation. Notably, BRD2 promoted the proteasome-dependent degradation of the bile acid receptor TGR5 without affecting its transcription, thereby reducing TGR5 protein abundance. Critically, tubule-selective knockdown of Tgr5 fully reversed the renoprotective, metabolic, and anti-ferroptotic benefits conferred by Brd2 deletion, leading to re-emergence of lipid overload and FAO suppression. Conversely, pharmacological activation of TGR5 with the selective agonist INT-777 rescued ferroptosis and restored FAO function in human proximal tubular cells overexpressing BRD2. Collectively, these findings delineate a BRD2-TGR5-FAO signaling axis as a central pathogenic driver of tubular lipotoxicity and ferroptosis in diabetic kidney injury, and position BRD2 inhibition as a mechanistically grounded therapeutic strategy for diabetic kidney disease.