eng Enviro Research Publishers Current Research in Nutrition and Food Science Journal 2347-467X 2322-0007 2026-05-25 14 2 26224 article Brijesh Lekhak 1 Minakshi Dutta 1 Nitin Kumar Singhal 2 Rama Prashat Govindarajalu 3 Navita Bansal 1 Suneha Goswami 1 Division of Biochemistry, ICAR-Indian Agricultural Research Institute, New Delhi, India Department of Food and Nutrition, National Agri-Food Biotechnology Institute, Mohali, India Division of Genetics and Plant Breeding, ICAR-Indian Agricultural Research Institute, New Delhi, India The present study investigates the bioavailability and gene regulatory effects of hydrolyzed plant protein blends compared to hydrolyzed whey protein in Caco-2 intestinal cells, aiming to evaluate their potential in managing hypercholesterolemia. Two plant protein isolate blends derived from chickpea, sesame, peanut, and mung bean in different ratios were enzymatically digested and assessed for protein content, solubility, cytotoxicity, amino acid transport, and gene expression. Hydrolyzed whey protein isolate (WPI) showed the higher total protein and essential amino acid (EAA) bioavailability, while hydrolyzed PlPIs demonstrated higher soluble protein content and superior non-essential amino acid (NEAA) absorption. All protein hydrolysates promoted Caco-2 cell proliferation without cytotoxic effects. Gene expression analysis revealed that both WPI and plant blends hydrolysates upregulated peptide transporter PepT1 and downregulated cholesterol metabolism gene SREBF2, indicating cholesterol-lowering potential via modulation of intestinal transport and lipid metabolic pathways. While WPI showed superior EAA delivery, PlPI-blends exhibited unique NEAA profiles, with PlPI-blend 2 particularly rich in glutamic acid, arginine, and aspartic acid, the amino acids linked to cardiovascular health and metabolic regulation. These findings highlight the promise of plant protein blends, particularly PlPI-blend 2, as functional food ingredients for promoting intestinal health and regulating cholesterol metabolism. https://www.foodandnutritionjournal.org/volume14number2/comparative-evaluation-of-plant-and-whey-protein-hydrolysates-bioavailability-intestinal-cellular-response-and-cholesterol-regulating-gene-expression-in-a-caco-2-model/ Bioavailability Caco-2 cell model Cholesterol homeostasis PepT1/SCL15A1 Plant protein isolates SREBF2