S100A9 as a Candidate Molecular Bridge in Hepato-Ocular Crosstalk

Increased S100 calcium-binding protein A9 (S100A9)-related signals have been reported in selected hepatic and ocular inflammatory settings. This structured narrative review evaluates S100A9-related species as candidate participants in hepato-ocular crosstalk. Across human, ocular fluid, animal, and cellular studies, the available findings provide context-specific support for disease-associated hepatic expression and ocular responsiveness, with stronger evidence for selected local S100A9-Toll-like receptor 4 (TLR4)-associated effects than for S100A9-specific receptor for advanced glycation end products (RAGE) signaling. Clinical associations involving metabolic dysfunction-associated steatotic liver disease, diabetic retinopathy, chronic liver disease, dry eye disease, and uveitis are heterogeneous and confounded. Interpretation is further limited by the non-equivalence of S100A9, S100A8/A9, calprotectin, and higher-order complexes. Current evidence, therefore, suggests that S100A9-related species may serve as exploratory indicators of inflammatory activity or contribute to local inflammatory amplification in selected settings, rather than acting as established liver-derived causal signals. Future studies should prioritize analyte-specific measurement, source tracing, and selective perturbation. S100A9 is best regarded as a testable candidate node within a broader metabolic-inflammatory network.