<p>The mitochondrial permeability transition pore (mPTP) is a critical regulator of mitochondrial function and cellular fate, serving as both a therapeutic target and a potential barrier in drug delivery. Prolonged or inappropriate mPTP opening is implicated in various pathological conditions, including cancer, neurodegenerative diseases, and cardiovascular disorders. Several mPTP-targeted molecules such as Cyclosporin A (for cardioprotection), MitoQ (for neurodegeneration), and Elamipretide (for mitochondrial myopathy) have advanced to Phase II/III clinical trials, demonstrating improvements in mitochondrial membrane potential, ATP recovery, and reduced oxidative damage. Emerging interventions including CRISPR-mediated PPIF inhibition and exosome-mediated delivery systems further highlight the potential for personalized, tissue-specific mitochondrial therapy. In addition, we review the therapeutic applications of mPTP modulation in conditions like ischemia-reperfusion injury, neurodegeneration, and cancer, and present case studies of successful interventions. Looking ahead, emerging strategies such as precision medicine and combination therapies are poised to improve the efficacy of mPTP-targeted treatments. This review concludes with a discussion on the future directions in mPTP research and the need for a deeper understanding of its complex regulatory mechanisms.</p>