Unlocking the therapeutic potential of human urinary kallidinogenase in stroke: a mini review

Stroke remains a leading cause of morbidity and mortality worldwide, with acute ischemic stroke (AIS) accounting for the majority of cases. Despite advancements in intravenous thrombolytic therapies such as recombinant tissue-type plasminogen activator (rt-PA), limitations including narrow therapeutic windows and variable recovery outcomes underscore the urgent need for adjunctive and alternative treatment options. Human Urinary Kallidinogenase (HUK), a serine protease derived from human urine, has emerged as a promising candidate owing to its multifaceted biological effects. This mini-review synthesizes evidence from preclinical and clinical studies, highlighting HUK’s neuroprotective, anti-inflammatory, anti-apoptotic, anti-oxidative, and angiogenic properties. Mechanistically, HUK modulates several critical signaling pathways, including inhibition of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) axis, activation of the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) and phosphoinositide 3-kinase/protein kinase B/Forkhead box O1 (PI3K/AKT/FoxO1) pathways, and regulation of oxidative stress through the nuclear factor erythroid 2-related factor 2/antioxidant response element (Nrf2/ARE) pathway. These mechanisms contribute to enhanced cellular survival and vascular repair. Additionally, HUK demonstrates synergistic effects when combined with agents such as rt-PA and dl-3-n-butylphthalide (NBP), resulting in improved neurological outcomes, reduced stroke recurrence, and enhanced recanalization rates. Beyond summarizing established mechanistic and clinical evidence, this review emphasizes future directions including the development of nanoparticle-based drug delivery systems, personalized treatment approaches guided by genetic and metabolic markers, and the exploration of HUK as a potential biomarker for vascular health and post-stroke complications. The integration of multi-omics technologies—such as transcriptomics, proteomics, and metabolomics—into future clinical trials may further elucidate HUK’s systemic effects and therapeutic interactions. Overall, this review provides a consolidated foundation for advancing research on HUK and advocates for large-scale, multicenter, randomized controlled trials to validate its efficacy and support its integration into comprehensive stroke management.