Processed phellodendri Chinensis cortex attenuates diabetic nephropathy via ferroptosis inhibition through GPX4/SLC7A11/Nrf2/HO-1 signaling pathway

Abstract

Diabetic nephropathy (DN) is a common complication of diabetes, increasingly linked to ferroptosis as an important underlying mechanism. While Phellodendri chinensis Cortex (PC) has shown renoprotective promise, the therapeutic value of its processed products remains unclear. We therefore compared raw PC (RPC) with three processed derivatives—salt-processed PC (SPC), salt praeparatum-processed PC (SP-PC), and depositum urinae praeparatum-processed PC (DUP-PC)—to evaluate whether processing enhances anti-ferroptotic activity and DN protection. UPLC-Q-TOF-MS profiling identified 51 chemical constituents, dominated by alkaloids in positive-ion mode and phenolic acids in negative-ion mode. In high-glucose-challenged HK-2 cells, SP-PC and SPC significantly outperformed RPC, demonstrating markedly enhanced inhibition of ferroptosis by lowering malondialdehyde (MDA), Fe²⁺, and reactive oxygen species (ROS) while restoring glutathione (GSH) and up-regulating key pathway components GPX4, SLC7A11, Nrf2, and HO-1. These findings were mirrored in streptozotocin (STZ)-plus-high-fat-diet DN rats, where SP-PC and SPC more effectively reduced serum creatinine (S-Cr), blood urea nitrogen (BUN), microalbumin-to-albumin ratio (MAU/ALB) and attenuated renal ferroptosis markers. Critically, both cellular and animal experiments consistently revealed that processing significantly enhances the anti-ferroptotic activity of PC. Thus, processed PC products—especially SP-PC and SPC—confer superior protection against DN by more effectively inhibiting ferroptosis via the GPX4/SLC7A11/Nrf2/HO-1 axis, highlighting processing as a key strategy to boost anti-ferroptotic efficacy in renal protection.