HE4 Serves as a Dual-Function Mediator in Chronic Kidney Disease：Biomarker of Renal Dysfunction and Instigator of TGF-β1-Driven Fibrosis

Chronic kidney disease (CKD) progression is fundamentally driven by renal fibrosis, yet sensitive biomarkers reflecting this pathological process remain elusive. This study systematically investigated the dual roles of human epididymis protein 4 (HE4) as both a functional biomarker and a pathogenic driver in 231 patients with CKD(stages G2-G5)and 66 healthy controls. Quantification of serum biomarkers revealed that HE4 levels increased 22.9-fold, from 48.8 pmol/L in controls to 1117.0 pmol/L in stage G5 CKD, demonstrating a robust inverse correlation with eGFR (r = -0.919, p < 0.001). Multivariate regression identified HE4 as a strong predictor of transforming growth factor-β1 (TGF-β1) elevation (β = 0.665; 5.187 pg/mL TGF-β1 increase per 1 pmol/L HE4), while mediation modeling delineated its stage-specific mechanisms: HE4 promoted α-smooth muscle actin (ACTA2) synthesis exclusively via TGF-β1-mediated pathways (ACME = 0.702), whereas collagen type I (COL1) expression exhibited bidirectional regulation involving TGF-β1-dependent induction (ACME = 0.951) and direct HE4 suppression (ADE = -0.564). Clinically, the HE4-ACTA2 panel achieved superior diagnostic accuracy for early-stage CKD (G2, AUC = 0.946), with 88.9% sensitivity and 89.4% specificity. These findings establish HE4 as a dual-function mediator in CKD pathogenesis. It not only mirrors glomerular filtration decline but also actively drives fibrogenesis through TGF-β1-positive feedback loops, positioning HE4 as both a precision diagnostic tool and a promising therapeutic target for anti-fibrotic interventions.