Immunomodulatory Effect of Tilapia ( <i>Oreochromis niloticus</i> ) Scale Gelatin Peptides in <i>RAW264</i> . <i>7</i> Macrophages and <i>Caenorhabditis elegans</i>

ABSTRACT Currently, small‐molecular‐weight collagen peptides are a research hotspot in functional factor development due to their high bioavailability and diverse bioactivities. In this study, gelatin was extracted from tilapia ( Oreochromis niloticus ) scales by hot water extraction, followed by pepsin hydrolysis and ultrafiltration to obtain the &lt; 3 kDa ultrafiltrated fraction of tilapia scale gelatin peptides (UTSGP). Through the evaluation of immunomodulatory activity and mechanisms, it was found that UTSGP significantly promoted the proliferation and phagocytic capacity of RAW264 . 7 macrophages. Specifically, its immunomodulatory activity was mediated by the nuclear factor‐κB (NF‐κB) pathway, which led to the increased production of tumor necrosis factor‐α (TNF‐α) and interleukin‐6 (IL‐6). In vivo studies in Caenorhabditis elegans ( C . elegans ) showed that UTSGP significantly extended lifespan, improved healthspan, and increased resistance to juglone‐induced oxidative stress. Further analysis revealed that UTSGP upregulated antioxidant genes ( sod‐3 , gst‐4 ) through the insulin/IGF‐1 signaling (IIS) pathway and enhanced innate immunity by modulating immune‐related gene expression. To our knowledge, this study is the first to demonstrate tilapia scales as a promising source of immunomodulators, showcasing the potential of their derived peptides for developing novel and efficient immunomodulatory functional foods.