A Urinary Peptide From Complement Factor B Alleviates Diabetic Renal Fibrosis by Inhibiting the HIF ‐1α‐Driven Glycolysis Pathway

ABSTRACT Diabetic kidney disease (DKD) remains a major cause of chronic kidney failure; early diagnosis and mechanistic understanding are still inadequate. Urinary peptidomics offers a noninvasive strategy to identify key peptides correlated with DKD pathology and underlying mechanisms. We profiled urinary peptides using CE‐MS/MS in three healthy controls, six diabetic patients without proteinuria, and 15 DKD patients. Target protein expression was validated in human kidney tissues and db/db mice. A synthetic peptide derived from complement factor B (CFB), identified as a top candidate, was functionally assessed in human and murine tubular cells, with its underlying mechanism explored via RNA‐sequencing and pharmacological modulation. We identified 4331 urinary peptides, revealing a distinct DKD‐specific signature enriched for proteins in the complement cascade and extracellular matrix pathways. Eight peptides strongly associated with disease severity and showed high diagnostic value. Among them, two bioactive peptides originating from CFB were significantly elevated in DKD. In vitro, the synthetic CFB peptide was efficiently taken up by tubular cells and attenuated fibrotic and oxidative stress. This nephroprotective effect was mediated through the suppression of the HIF‐1α/glycolysis axis, as the effect was reversed by an HIF‐1α activator (DMOG) and restored by a glycolysis inhibitor (2‐DG). Our study delineates a DKD‐specific urinary peptidome and identifies a bioactive CFB‐derived peptide with potent antifibrotic and antioxidative properties. The findings support its potential as both a biomarker and a therapeutic candidate, highlighting an interplay between complement activation and metabolic dysregulation in the kidney.