Synergistic genomic design and thermal processing mitigate anti-nutritional constraints to enhance the nutritional efficacy of diploid potatoes.

Global food security demands sustainable alternatives to the conventional feed ingredient wheat. Nutrient-dense diploid potatoes (HQP) represent candidates due to their enriched phytochemical profiles, including high levels of vitamin C and lutein. However, their dietary utilization is constrained by endogenous anti-nutritional factors (ANFs), primarily solanine and trypsin inhibitors. Using a zebrafish model, we demonstrate that these ANFs trigger intestinal dysbiosis and an oxidative-inflammatory response. Mechanistically, this adverse gut environment suppresses the mTOR pathway, as evidenced by reduced phosphorylation of S6K1 and 4E-BP1, ultimately leading to growth depression. To address this toxicological barrier, we integrated genetic selection (diploid HQP) with thermal processing (steam-cooking). Quantitative analysis revealed that while thermal processing effectively reduced ANF concentrations to physiologically safe levels, the HQP matrix retained significantly higher residual concentrations of vitamin C, lutein, and zeaxanthin compared to conventional tetraploid (C88) and wheat-based diets. Mechanistically, protein-level evidence confirmed that this processed HQP formulation promoted the total NRF2 and suppressed NF-κB P65 accumulation. This metabolic shift attenuated inflammation, reactivated mTOR signaling, and subsequently enhanced growth performance and digestive capacity. Our findings establish a mechanistic framework demonstrating how integrated genomic design and processing strategies facilitate the functional utilization of high-phytochemical crops in sustainable food systems.