S100 proteins in kidney disease: Inflammatory biomarkers, pathogenic mechanisms and therapeutic prospects (Review)

The S100 protein family, particularly the calprotectin heterodimer S100A8/A9, is increasingly recognized as both an inflammatory readout and a context‑dependent mediator of kidney injury. Selected extracellular S100 proteins function as damage‑associated molecular patterns released during cellular stress, leukocyte activation and tissue injury. They can amplify sterile inflammation through the receptor for advanced glycation end‑products (RAGE), Toll‑like receptor 4 (TLR4) and related downstream pathways, although receptor usage and biological effects vary by cell type and disease setting. The present review examines S100 proteins in kidney disease across three related domains: Clinical biomarkers, disease mechanisms and therapeutic translation. Current evidence most strongly supports urinary S100A8/A9 for distinguishing intrinsic from pre‑renal acute kidney injury; circulating S100A8/A9 and S100A12 have mainly been studied as markers of inflammatory and cardiovascular risk in chronic kidney disease. S100‑associated signaling has been implicated in leukocyte recruitment, mesangial and macrophage activation, podocyte injury, tubular stress, tubulointerstitial fibrosis and uremia‑associated vascular calcification. Emerging studies also describe stress‑regulated and intracellular S100 functions, including gasdermin E (GSDME)‑regulated signal transducer and activator of transcription 3 (STAT3) signaling that controls S100A7A, S100‑annexin complexes and S100A16‑driven Wnt/β‑catenin or endoplasmic reticulum stress. However, therapeutic evidence remains largely preclinical, and clinical translation is constrained by ligand redundancy, disease heterogeneity and incomplete prospective validation. S100 proteins may therefore contribute to biomarker panels and targeted interventions, but their clinical utility requires prospective validation and clear separation of receptor‑mediated from intracellular effects.