## 1 Introduction  
The bio-based food additives obtained from upcycling grapefruit peels can be used mainly in the food industry as natural antioxidant and antimicrobial alternatives. Additionally, these ingredients also show anti-inflammatory potential, underscoring their potential as a nutraceutical. Grapefruit (GF) processing generates significant nutrient and economic losses due to the production of 50% by-products, primarily peels. GF peels are a rich and sustainable source of bioactive compounds (DCs), such as essential oils (EOs) and phenolic compounds. Thus, finding value-added solutions based on a circular economy is paramount. This research aims to assess the antioxidant, anti-inflammatory, and antimicrobial properties of a hydroethanolic polyphenol-rich extract from crude GF peels (GF-CE), essential oil (GF-EO), and polyphenol-rich extract from GF peels after essential oil extraction (GF-PE). The GF-CE and GF-PE showed high concentrations of naringenin (7.71 and 48.60 mg/g dry extract (DE)), narirutin (15.03 and 28.73 mg/g DE), and hesperidin (0.67 and 0.29 mg/mL), respectively. Extracting firstly EOs from GF improved the release of phenolic acids (p-coumaric, ferulic, and chlorogenic acid). The GF-CE exhibited stronger free radical scavenging activity mainly in DPPH (IC50 = 75.69 \(\pm\) 0.81 ug/mL) than GF-EO (1271 \(\pm\) 0.85 ug/mL) and GF-PE (113.45 \(\pm\) 0.85 ug/mL). The GF-EO demonstrated moderate antimicrobial activity against Gram-positive bacteria compared to the reference standard (amoxicillin) and strong activity against the yeast _Candida albicans_ (inhibition zone of 16 mm). The major compounds in the GF-EO included D-limeonene (25%), noonductance (24%), and \(\beta\)-pinene (8%). Both polyphenol-rich extracts showed promising activities as COX1 and COX2 inhibitors with IC50 values of 25 \(\pm\) 0.1 and 0.28 \(\pm\) 0.00 ug/mL (compared to celecoxib (97.5 \(\pm\) 0.1 and 0.31 \(\pm\) 0.01 ug/mL) and indomethacin (6.25 \(\pm\) 0.00 and 0.52 \(\pm\) 0.01 ug/mL) as the standards), respectively. The study concludes that GF peels are a valuable source of SCs with significant bioactivities, offering a sustainable multi-cascade approach to recovering value-added compounds from GF peels in alignment with circular economy principles and open opportunities as functional ingredients for food applications. grapefruit peel; polyphenols; essential oil; circular economy; bioactivities  
## 1 Introduction  
Citrus fruits are widely consumed worldwide and have received considerable attention recently due to high levels of bioactive compounds (BCs), such as phenolic compounds and essential oils, which showed several human health-promoting benefits [1]. According to recent FAO statistical data, in 2022, the genus Citrus had an annual production of about 166.30 million tons, whereas the worldwide production of grapefruits (_Citrus paradisi_) was 9.76 million tons during the marketing year 2021/2022 [2; 3]. The Mediterranean region is one of the main GF producers (30% of total production), where Turkey, Tunisia, Spain, and Egypt are among the top countries in the ranking [3]. Consumers highly appreciate grapefruit (GF) due to its abundance of nutrients and phytochemicals, which are valuable additions to a nutritious diet. They are consumed either fresh or processed [4]. Nevertheless, the processing results in juice and by-products consisting mainly of peels, pulps, and seeds, accounting for half of the fruit weight [5]. Thereby, GF processing generates a vast amount of waste generally used in composting and animal feed. In the worst cases, it is burned or dumped in landfills, which results in serious environmental issues and financial losses for the companies [6]. To overcome these unsustainable actions, a great industrial and scientific interest has risen to upcycle these side streams into high-value-added products [7]. Peels remain the primary by-product of GF processing and contain several phytochemicals, such as flavonoids, phenolic acids, vitamin C, carotenoids, and terpen [8].