Piperine: From Green Extraction to Clinical Translation-A Review.

BACKGROUND: Piperine has diverse pharmacological and bioenhancing activities, but poor aqueous solubility, variable exposure, interaction liability, and discontinuity across production, formulation, and clinical evaluation limit translation. This review integrates these frequently separated stages. METHODS: A structured narrative PubMed search covered English-language studies published from 1 January 2021 to 27 April 2026, supplemented by ClinicalTrials.gov records checked through 13 June 2026, backward citation searching, and selected earlier seminal studies. Evidence was synthesized by experimental level, methodological limitations, and translational relevance. KEY FINDINGS: In one solvent-circulation study, response surface methodology optimization increased the reported piperine yield from 3.87% to 5.20% of dry material, although external batch or production-scale validation was not reported. In rats, a solid piperine self-nanoemulsifying drug delivery system produced 4.92-fold higher relative oral bioavailability than pure piperine dispersion, without human pharmacokinetic validation. Preclinical studies reported anticancer, anti-inflammatory, neuroprotective, anti-infective, and metabolic effects. Head-and-neck cancer-cell IC50 ranges were 102.8-176.0 µM in HEp-2 cells and 121.0-249.9 µM in SCC-25 cells, without exposure-matched in vivo confirmation. Published trials included COVID-19 (n=140), sepsis (n=66), and ischemic stroke (66 randomized; 56 completed); these trials evaluated curcumin-piperine combinations. A 2025 meta-analysis of 18 curcuminoid-piperine trials reported pooled reductions in AST and IL-6 but not ALT, ALP, CRP, or TNF-α. CHALLENGES: Extraction comparisons were limited by differences in botanical material, process conditions, and analytical methods. Other gaps included production-to-formulation continuity, stand-alone human exposure-response data, substrate-dependent interactions, long-term safety, and predominantly small or combination-based clinical studies. CONCLUSION: Current evidence supports further development but not established stand-alone pharmaceutical efficacy. Translation requires standardized materials, scalable production, exposure-guided formulations, longer-term safety and interaction studies, and adequately powered trials with piperine-specific comparators.