SPP1 as a predictive biomarker and therapeutic target in fibrotic

Background: Bridging genome-wide association studies (GWAS) for chronic renal allograft dysfunction (CAD) to clinical outcomes remains challenging due to undefined functional genes and cellular mechanisms. We aimed to identify functional genes implicated in CAD progression and evaluate their utility as biomarkers and therapeutic targets in transplant settings.
Methods: We integrated human genomics from the largest kidney disease GWAS, single-cell and spatial transcriptomics from Kidney Precision Medicine Project cohorts (n=79 samples), and clinical proteomics across multiple independent cohorts including the UK Biobank (N=6,500) and a cohort of kidney transplant recipients (N=400). Plasma SPP1 was identified and assessed for associations with CAD severity, eGFR, interstitial fibrosis/tubular atrophy (IFTA), and post-transplant outcomes. Therapeutic targeting used ASK8007, an anti-SPP1 monoclonal antibody, delivered via hyaluronic acid-coated lipid nanoparticles in kidney transplant models.
Results: Through multi-omic integration, SPP1 emerging as a central candidate, enriched in renal tubular epithelium and linked to the locus (rs117078377; P=2.66×10⁻⁹). Single-cell and spatial transcriptomic analyses revealed a novel pathogenic mechanism in which degenerative collecting tubules (dCNT), rather than macrophages, are the primary source of SPP1 in CKD. Specifically, dCNT-derived SPP1 recruits CD44⁺ SPP1⁺ macrophages through the SPP1-CD44 axis. Conditional knockout mice of tubular SPP1 demonstrated that epithelial-derived SPP1 exerts a more dominant pro-fibrotic effect than macrophage-derived SPP1, thus expanding the traditional immune-centric model into a dual epithelial–immune model of CKD fibrosis. Plasma SPP1 was validated as an exceptional non-invasive biomarker for kidney fibrosis across independent clinical cohorts. SPP1 outperformed nine conventional biomarkers, including cystatin C (AUC 0.96 vs. 0.76), and identified post-transplant graft deterioration up to 3 months earlier than eGFR or creatinine. Notably, SPP1 maintained predictive value regardless of dialysis or transplant status, addressing a critical limitation of existing biomarkers. To overcome pharmacokinetic limitations that hindered prior clinical development of ASK8007 in rheumatoid arthritis, we engineered PLAG-coated lipid nanoparticles for CNT-targeted, sustained-release delivery of ASK8007. This platform extended systemic circulation, protected the antibody from degradation, and selectively enriched the delivery within fibrotic renal niches, resulting in significant fibrosis reduction and preserved kidney function across multiple CAD models.
Conclusions: This study presents SPP1 as a central mediator of CAD progression, a clinically actionable predictive biomarker, and a promising therapeutic target for precision interventions in kidney transplantation. The findings challenge the conventional immune-centric paradigm, propose a dual epithelial–immune model of fibrosis, and introduce a novel therapeutic delivery strategy for targeted anti-SPP1 therapy.