Gut Microbial Postbiotics as Potential Therapeutics for Lymphoma: Proteomics Insights of the Synergistic Effects of Nisin and Urolithin B Against Human Lymphoma Cells

Lymphoma continues to pose a significant global health burden, highlighting the urgent need for novel therapeutic strategies. Recent advances in microbiome research have identified gut microbiota-derived metabolites, or postbiotics, as promising candidates in cancer therapy. This study investigates the antiproliferative and mechanistic effects of two postbiotics, Nisin (N) and urolithin B (UB), individually and in combination, against the human lymphoma cell line HKB-11. Moreover, this study evaluated cytotoxic efficacy and underlying molecular pathways using a comprehensive experimental approach, including Alamar Blue assay, combination index (CI) analysis, flow cytometry, reactive oxygen species (ROS) quantification, and bottom-up proteomics. N and UB displayed notable antiproliferative effects, with IC₅₀ values of 1467 µM and 87.56 µM, respectively. Importantly, their combination at a 4:6 ratio demonstrated strong synergy (CI = 0.09 at IC₉₅), significantly enhancing apoptosis (p < 0.0001) and modulating oxidative stress. Proteomic profiling revealed significant regulation of key proteins related to lipid metabolism, mitochondrial function, cell cycle control, and apoptosis, including upregulation of COX6C (Log₂FC = 2.07) and downregulation of CDK4 (Log₂FC = –1.26). These findings provide mechanistic insights and underscore the translational potential of postbiotics in lymphoma treatment. Further preclinical and clinical investigations are warranted to explore their role in therapeutic regimens.