Bio-Assay-Guided Study of Chaenomeles japonica–Cytokine Modulation by Fruit Aqueous Extract In Vitro in Connection with Its Processing with Enzymatic and Microbial Additives

<b>Background/Objectives</b>: Phytochemicals from <i>Chaenomeles japonica</i> (CJ) (Thunb.) Lindl. ex Spach, a plant belonging to the Rosaceae family, are recognized for their potential to inhibit enzymes associated with diabetes, obesity, neurodegeneration, and inflammation. However, the influence of constituents from different plant parts on cytokine secretion has not yet been explored or comparatively analyzed. <b>Methods</b>: This study aimed to evaluate the anti-inflammatory potential of CJ by assessing its effects on chemokine and cytokine secretion, including interleukin (IL)-8, IL-1β, TNF-α, IL-6, and IL-10. Extracts from various plant parts (fruit, seed, flower, and leaf) were examined for their ability to modulate cytokine production in human neutrophils (PMNs). Among them, the aqueous fruit extract exhibited the strongest activity and was subsequently tested on peripheral blood mononuclear cells (PBMCs) and the human intestinal epithelial cell line Caco-2. The extract was also subjected to in vitro gastrointestinal digestion to assess the stability and bioactivity of its metabolites. The phytochemical composition of CJ preparations was characterized by ultra-high-performance liquid chromatography coupled with diode-array detection and tandem mass spectrometry (UHPLC-DAD-MS/MS). <b>Results</b>: The aqueous fruit extract significantly reduced the secretion of pro-inflammatory cytokines across all tested models. Fractions obtained after in vitro digestion also inhibited IL-8 release in Caco-2 cells. <b>Conclusions</b>: The most active fractions were rich in flavan-3-ols and proanthocyanidins. These findings indicate that CJ fruit possesses notable anti-cytokine properties and may serve as a promising natural source for developing functional food.