Enterolactone effectively resolves intimal inflammation and redresses atherosclerosis by ameliorating the gut microbiome and modulating lipid metabolism via the Keap1/Nrf2/GPX4 pathway.
Enterolactone significantly reduced arterial plaque area in ApoE-/- mice fed a high-fat diet.
Enterolactone significantly improved lipid metabolism in atherosclerotic mice.
Enterolactone attenuated ferroptosis occurring in the vascular intima and facilitated antioxidant mechanisms in atherosclerotic mice.
Enterolactone suppressed H2O2-induced ferroptosis and lipid peroxidation in HUVECs via the Keap1/Nrf2/GPX4 pathway.
Nrf2 knockdown attenuated the therapeutic effect of enterolactone on HUVEC ferroptosis.
Enterolactone massively altered gut microbiota composition toward a curative outcome, elevating the abundance of beneficial bacteria including SCFA-producing taxa.
Enterolactone reduced the inflammatory response in arterial tissue of atherosclerotic mice.
This research suggests that enterolactone, a natural compound produced when gut bacteria transform plant lignans from foods like flaxseeds and whole grains, can significantly reduce the progression of atherosclerosis (hardening and narrowing of arteries due to plaque buildup). Using mice genetically predisposed to atherosclerosis and fed a high-fat diet, the researchers found that enterolactone reduced arterial plaque size, lowered blood lipid levels, decreased inflammation in the artery walls, and protected the cells lining blood vessels from a type of cell death called ferroptosis—which involves damaging iron-related oxidative stress. The compound achieved these effects by activating a key protective cellular pathway called Keap1/Nrf2/GPX4, which helps cells defend against oxidative damage. In laboratory experiments using human blood vessel cells (HUVECs), the researchers confirmed that enterolactone directly protects endothelial cells from oxidative injury and ferroptosis through this same Nrf2-dependent pathway—and that blocking Nrf2 reduced enterolactone's protective effects. Additionally, enterolactone substantially changed the gut microbiome in treated mice, increasing beneficial bacteria that produce short-chain fatty acids (SCFAs), which are known to have anti-inflammatory and metabolic benefits. This research suggests that enterolactone, which humans obtain naturally through diet and gut bacterial activity, may offer a multi-pronged approach to combating atherosclerosis by simultaneously improving lipid metabolism, reducing vascular inflammation, protecting blood vessel cells, and favorably reshaping the gut microbiome. This could be relevant given that current atherosclerosis therapies do not always achieve satisfactory outcomes, though further research in humans would be needed to translate these findings into clinical practice.
Chai S, Zhang Y, Guo Y, Cao D, Wang J, Yan Y, et al.. (2026). Enterolactone mitigates atherosclerosis by facilitating resolution of ferroptosis-associated intimal inflammation via the Keap1/Nrf2/GPX4 pathway.. Phytomedicine : international journal of phytotherapy and phytopharmacology. https://doi.org/10.1016/j.phymed.2026.158178