Antithrombin in Hyperuricemic Nephropathy: Unveiling Its Noncanonical Renoprotective Roles and Therapeutic Repurposing Potential.

The pathogenesis of hyperuricemic nephropathy (HN) is increasingly linked to a self-perpetuating cycle of thromboinflammation. This process begins with hyperuricemia-induced endothelial dysfunction, which activates both the coagulation cascade and inflammatory pathways, notably the pyrin domain-containing protein 3 inflammasome. This creates a vicious cycle of which inflammation promotes coagulation and coagulation products further amplify inflammation, ultimately leading to renal microvascular thrombosis, ischemia, and progressive fibrosis. This review critically examines the therapeutic potential of antithrombin (AT) in interrupting this pathogenic axis. AT, a key serine protease inhibitor, is central to physiological anticoagulation. Beyond its canonical role in neutralizing thrombin and Factor Xa (FXa), AT exerts potent anti-inflammatory and endothelial-stabilizing effects, primarily mediated through interactions involving its D-helix domain. Compelling preclinical evidence from models of sepsis, ischemia-reperfusion, and diabetic nephropathy demonstrates that AT can attenuate inflammation, improve microcirculation, and reduce fibrosis. We hypothesize that in HN, augmenting AT levels could simultaneously dampen thrombin generation, quell the associated inflammatory response, protect the endothelium, and thereby mitigate the structural drivers of renal decline. This positions AT as a unique multi-target candidate for disease modification. However, this promising hypothesis remains largely untested in HN-specific models. Current support is extrapolated from related conditions sharing thromboinflammatory pathology. Therefore, this review synthesizes the mechanistic rationale, clearly delineates established science from translational hypothesis, and identifies the crucial experimental gaps-particularly regarding optimal dosing, timing, and direct validation of efficacy in HN-that must be addressed to evaluate AT's repurposing as a targeted therapy for hyperuricemic kidney injury.