CYP1B1: A Context-Dependent Regulator of Metabolism in Diabetic Kidney Disease

Diabetic kidney disease (DKD) is a prevalent diabetic microvascular complication driven by metabolic dysregulation, inflammation, oxidative stress, and fibrosis. As a key metabolic enzyme, cytochrome P450 1B1 (CYP1B1) modulates multiple signaling cascades in DKD. This article first outlines CYP1B1’s gene architecture, tissue distribution, and regulatory profiles and then dissects its multifaceted roles in DKD: reshaping metabolite profiles via arachidonic acid, retinoic acid, and estrogen axes; tuning inflammation and fibrosis through AHR/nuclear factor-κB cross talk; and orchestrating bidirectional control of renal ferroptosis via cAMP and arachidonic acid. Deciphering this network offers new insights into DKD pathogenesis and therapeutic target discovery. We also evaluate CYP1B1 inhibitors’ translational potential, noting that current evidence remains insufficient for clinical use of selective inhibitors or combination regimens. Notably, CYP1B1 exerts context-dependent dual effects: sustaining epoxyeicosatrienoic acid–related renoprotective signaling while driving 4-hydroxyestradiol quinone generation and ferroptosis, which are amplified under diabetic metabolic disturbance. This article, thereby, frames all discussions around this unique bidirectional paradigm, mapping key unresolved gaps to guide future DKD translational research. Article Highlights This study systematically dissects the regulatory role of CYP1B1 in the pathogenesis of diabetic kidney disease (DKD). CYP1B1 participates in the progression of DKD by mediating the metabolism of arachidonic acid, retinoic acid, and estradiol, as well as the process of ferroptosis. Its 4-OHE2 quinone metabolites and proferroptotic effect promote renal injury, while it is associated with the maintenance of renoprotective signaling. The net effect of CYP1B1 is regulated by substrate type, cell type, and disease stage, and it can serve as an epigenetic marker and gut-kidney axis mediator in DKD.