Pathophysiological significance of the TRPM2 ion channel as a potential target in cancer, neurological disorders, and ischemia/reperfusion injury.

The transient receptor potential melastatin 2 (TRPM2) ion channel is a redox-sensitive, non-specific cation channel that plays a vital role in the regulation of Ca2+ homeostasis and cellular functions in response to oxidative stress. However, aberrant expression of TRPM2 is associated with various pathological conditions. Overexpression of TRPM2 promotes cell survival in multiple malignancies, including neuroblastoma, lung, prostate, stomach, and pancreatic cancers. TRPM2 also mediates different neurological disorders, such as Alzheimer's disease (AD), Parkinson's disease (PD), and epilepsy, and contributes to ischemia/reperfusion (I/R) injury. This review provides a comprehensive summary of the pathophysiological significance of TRPM2, covering the structural features, regulation, and oxidative stress signaling, with a major focus on the mechanistic pathways that link TRPM2 to these diseases. We discuss the therapeutic potential of TRPM2, its long non-coding antisense RNA (TRPM2-AS), and provide a comprehensive overview of currently available TRPM2 inhibitors, including adenosine diphosphate ribose (ADPR) analogs, small molecules, and peptides. This review covers an in-depth analysis of the structural activity relationships (SAR), pharmacokinetic (PK) properties of these TRPM2 inhibitors, detailing their preclinical efficacy studies, and outlining their shortcomings. Overall, we conclude that TRPM2 represents a promising drug target for effective therapies in several major disease indications.