| Summary: | The relationship between dietary constituents and the onset and prevention of colorectal cancer (CRC) is constantly growing. Recently, the antineoplastic profiles of milk and whey from Mediterranean buffalo (<i>Bubalus bubalis</i>) have been brought to attention. However, to date, compared to cow milk, the potential health benefits of buffalo milk exosome-miRNA are still little explored. In the present study, we profiled the exosomal miRNA from buffalo milk and investigated the possible anticancer effects in CRC cells, HCT116, and HT-29. Results indicated that buffalo milk exosomes contained higher levels of miR-27b, miR-15b, and miR-148a compared to cow milk. Mimic miR-27b transfection in CRC cells induced higher cytotoxic effects (<i>p</i> < 0.01) compared to miR-15b and miR-148a. Moreover, miR-27b overexpression in HCT116 and HT-29 cells (miR-27b<sup>+</sup>) induced apoptosis, mitochondrial reactive oxygen species (ROS), and lysosome accumulation. Exposure of miR-27b<sup>+</sup> cells to the bioactive 3kDa milk extract aggravated the apoptosis rate (<i>p</i> < 0.01), mitochondrial stress (<i>p</i> < 0.01), and advanced endoplasmic reticulum (ER) stress (<i>p</i> < 0.01), via PERK/IRE1/XBP1 and CHOP protein modulation (<i>p</i> < 0.01). Moreover, GSK2606414, the ER-inhibitor (ER-i), decreased the apoptosis phenomenon and XBP1 and CHOP modulation in miR-27b<sup>+</sup> cells treated with milk (<i>p</i> < 0.01 vs. miR-27b<sup>+</sup>+Milk), suggesting the ER stress as a cell-death-aggravating mechanism. These results support the in vitro anticancer activity of 3kDa milk extract and unveil the contribution of miR-27b in the promising beneficial effect of buffalo milk in CRC prevention.
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