BACKGROUND:Valorizing sugar-rich food waste in biorefineries offers a sustainable route to bio-based products. Grapefruit peel (GP), representing about 50% of the fruit's weight, is rich in sugars (soluble and insoluble) and polyphenols such as flavonoids. The present study investigates an integrated green extraction strategy using high-intensity focused ultrasound (HIFU) and enzymatic hydrolysis (EH) to recover phenolic compounds and sugars from GP. RESULTS:Vacuum-drying preserved extractability and sugars release with the carbohydrases evaluated. Using dried GP at 10% (DW/v), EH incorporating lytic polysaccharide monooxygenases yielded >60 g L-1 reducing sugars and 1-2.3 g L-1 phenolics (gallic acid equivalents, GAE) after 24 h. Optimal HIFU conditions (46-57% amplitude, 40-59% ethanol v/v, 11-32 min) matched the phenolic yield of conventional extraction (20 mg GAE g-1 DW) but improved antioxidant capacity (53% 2,2-diphenyl-1-picrylhydrazyl inhibition vs. 15%) at the same time as reducing solvent use (from 48 to 10-14.8 mL g-1 DW) and time (2 h to 11-32 min). Liquid chromatography-tandem mass spectrometry profiling identified key flavonoids and coumarins. Extracts exhibited selective cytotoxicity toward HeLa and MCF7 cells and antimicrobial effects against Escherichia coli at high concentrations. The solid residue from optimal HIFU was subsequently subjected to EH, yielding slightly less sugars and minimal phenolic compounds compared to the enzyme-only process. CONCLUSION:Sequential HIFU-EH offers an efficient, sustainable approach to valorize GP, reducing solvent and time requirements at the same time as co-producing bioactive phenolics and fermentable sugars in separate steps, thereby avoiding phenolic inhibition during subsequent biological steps. The process enhances antioxidant and antimicrobial properties and supports potential applications in food, nutraceutical and biorefinery sectors. © 2025 The Author(s). Journal of the Science of Food and Agriculture published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.
