Expanding Therapeutic Horizons: A Review of Tadalafil’s Off-Label Applications and Pharmacological Profile

Phosphodiesterase type 5 inhibitors (PDE5-Is), have initially revolutionized the treatment of erectile dysfunction (ED). Among these, Tadalafil (TDL) stands out due to its unique pharmacokinetic properties and extended half-life. This review explores the multifaceted pharmacological effects of TDL, emphasizing its mechanisms of action beyond PDE5 inhibition. TDL elevates intracellular cGMP by blocking its degradation, thereby enhancing nitric oxide (NO)-mediated vasodilation and signal transduction. Emerging evidence reveals that TDL exerts significant antioxidant, anti-inflammatory, anti-apoptotic, and anti-fibrotic effects, alongside notable immune-modulatory, antinociceptive, and neuroprotective actions. Furthermore, TDL demonstrates uroprotective, renoprotective, cardioprotective, gastrointestinal, reproductive, and skeletal muscle/bone-supporting benefits in various pathological models. Its efficacy in improving cognitive performance, ameliorating ischemia-reperfusion injury, and modulating immune checkpoints positions TDL as a promising adjunct in oncology. Additionally, the drug’s influence on insulin signaling, mitochondrial function, and the NO/cGMP/PKG pathway underpins its therapeutic versatility across metabolic, vascular, and degenerative diseases. Given its broad safety profile and extensive systemic effects, TDL holds considerable promise for repurposing in multiple clinical contexts. This review underscores the therapeutic potential of TDL beyond its conventional use in ED, advocating further clinical investigation into its expanding spectrum of pharmacological applications.