Aspirin: Classical Molecular Pharmacology, Off-Label; Repurposing Potentials and Benefit-Risks

Aspirin is a century-old classic nonsteroidal anti-inflammatory drug (NSAID) that has been clinically used as an antipyretic, an analgesic, an anti-inflammatory and an anti-rheumatic. The principle clinical activity is its ability to inhibit cyclooxygenase (COX), which blocks the production of prostaglandins, reducing pain, fever and excessive inflammatory response in rheumatic and inflammatory disorders. In addition, progress in pharmacology and molecular biology has shed further light on the mechanisms of action of aspirin and highlighted the potential for aspirin to be used as a drug repurposing target. In addition to the well-known COX pathway, aspirin has many non-canonical bioactivities, such as anti-tumor activity, intervention in metabolic disorders, neuroprotection in neurodegenerative diseases, COX independent anti-inflammatory activity and regulation of cellular anti-senescence activity. These novel pharmacological properties have been supported by a wealth of pre-clinical data and retrospective observational clinical evidence but remain to be unequivocally confirmed with large scale prospective randomized controlled trials. In this review, the traditional molecular actions of aspirin, the newly reported therapeutic indications during the last five years, and the critical safety concerns of gastrointestinal mucosal damage and systemic bleeding will be described, and unresolved issues regarding optimal doses, target patient groups and the intricate benefit-risk ratio will be analyzed. Future research avenues are also explored such as novel targeted formulations and strategies of personalized medicine, tailored to individual genetic traits and clinical phenotypes. This book offers a theoretical foundation for aspirin-oriented translational research and offers rational evidence-based guidance to extend its clinical therapeutic role.