Estrogen receptors and the NRF2 pathway: bridging hormonal regulation and stress response in the gut

Estradiol, the most potent endogenous estrogen, exerts its biological effects primarily through estrogen receptors, which are expressed in nearly all tissues, including the intestine. Beyond its established roles in reproductive physiology and metabolism, estradiol also influences intestinal motility, barrier integrity, and nutrient absorption. Emerging evidence further indicates that estrogen signaling intersects with NRF2, a central regulator of cellular stress responses and detoxification. This interplay suggests that estrogen may contribute to gut homeostasis by limiting cellular damage and enhancing adaptive defense mechanisms. Accordingly, a clearer understanding of estrogen receptor-NRF2 crosstalk in the intestine may inform new therapeutic strategies for gastrointestinal and metabolic disorders. In this review, we synthesize current evidence on estrogen signaling and NRF2 function in the gastrointestinal tract, with particular emphasis on their emerging interactions and potential roles in intestinal homeostasis. We also integrate findings from extra-intestinal models to outline regulatory networks that may shape estrogen-NRF2 crosstalk in the gut and discuss the potential contributions of the microgenderome and the possible clinical relevance of estrogen receptor-associated NRF2 modulation.