Elucidating the therapeutic mechanisms of Erzhi Pills against adenine-induced chronic kidney disease: A multi-omics study.

Abstract

Erzhi Pill (EZP), a classic traditional Chinese medicine formula, shows promise in ameliorating chronic kidney disease (CKD), yet its comprehensive mechanisms remain elusive. This study aimed to systematically decipher the therapeutic effects and underlying molecular mechanisms of EZP against CKD by employing an integrated multi-omics approach combined with experimental validation. In an adenine-induced CKD rat model, EZP significantly alleviated renal dysfunction, pathological injury, oxidative stress, and inflammation. Integrated analysis of serum metabolomics, renal lipidomics, and renal transcriptomics revealed that the renoprotective effects of EZP were primarily associated with the modulation of arachidonic acid metabolism, PPAR signaling pathway, and sphingolipid signaling pathway. Experimental validation demonstrated that EZP exerted anti-inflammatory effects by bidirectionally regulating the arachidonic acid metabolic network-downregulating pro-inflammatory enzymes (COX-2, LOX) while upregulating the anti-inflammatory enzyme CYP2J2. Furthermore, EZP mitigated oxidative stress and lipotoxicity by activating the PPARα/CPT1A pathway and upregulating HO-1 expression. Finally, EZP suppressed renal fibrosis by inhibiting the SPHK1/S1PR1 signaling axis and reversing epithelial-mesenchymal transition (EMT). Collectively, our findings illustrate that EZP ameliorates CKD progression through multi-target mechanisms involving coordinated anti-inflammatory, antioxidant, and anti-fibrotic activities. This study not only provides a scientific basis for the clinical application of EZP but also showcases the power of integrated omics strategies in elucidating the complex mechanisms of traditional medicines.