Novel Roles of Urokinase- and Tissue-Type Plasminogen Activators in Substance Use Disorders: A Narrative Review of Molecular Mechanisms and Translational Perspectives

The plasminogen activator system (PAS), comprising urokinase-type plasminogen activator (uPA), tissue-type plasminogen activator (tPA), their receptors, and endogenous inhibitors, has been extensively investigated for its established roles in haemostasis, fibrinolysis, vascular remodelling and extracellular matrix (ECM) homeostasis. Increasing evidence indicates that the functions of the PAS extend well beyond the cardiovascular system and have important regulatory roles in neuronal plasticity, synaptic remodelling, neuroinflammation, and neurotrophic signalling. These processes are increasingly recognized as central contributors to the neurobiological adaptations underlying substance use disorders (SUDs). In this narrative review, we critically evaluate the current evidence regarding the involvement of the PAS in SUDs, with particular emphasis on the molecular and cellular mechanisms through which uPA and tPA influence addiction-related neuroplasticity. The available literature is predominantly derived from preclinical studies, while direct clinical evidence remains limited. Experimental findings support roles for uPA and tPA in modulating reward-related circuitry, behavioural sensitization, relapse-like behaviours, and neurotrophic signalling, including potential interactions with brain-derived neurotrophic factor (BDNF)-related pathways, although the relative contributions of plasmin-dependent and plasmin-independent pathways remain incompletely understood. We also discuss the potential involvement of the PAS in neuroinflammatory responses and synaptic remodelling, together with the challenges associated with translating these findings into clinically relevant biomarkers or therapeutic strategies. Finally, we identify important gaps in current knowledge, including the need for independent replication, mechanistic clarification, and well-designed human studies to establish the clinical relevance of PAS dysregulation in addiction. Collectively, the available evidence supports a modulatory role for the PAS in addiction-related neurobiology and provides a rationale for further translational investigation, while highlighting that PAS-directed therapeutic approaches remain experimental and require substantial preclinical and clinical validation.