Piezo1 Regulates ZnT1-Mediated Zinc Homeostasis in Ulcerative Colitis

Ulcerative colitis (UC) is characterized by inflammatory damage of the intestinal epithelium, contributed by activation of Piezo-type mechanosensitive ion channel component 1 (Piezo1) and dysregulation of zinc homeostasis, critically maintained by zinc transporter 1 (ZnT1). Interactions between Piezo1 and ZnT1-mediated zinc homeostasis and effects on barrier function during colitis were investigated in this study. Inflammation-induced barrier disruption was modeled in vivo using dextran sulfate-treated mice and in vitro using lipopolysaccharide-treated Caco-2 cells. Intestinal epithelial cell (IEC)-specific Piezo1 knockout in mice, small interfering RNA-mediated silencing, Piezo1 agonist and antagonist, zinc ion (Zn2+) supplement and chelator in Caco-2 cells were utilized to manipulate activities of Piezo1 and ZnT1. Suppression of Piezo1 in IECs alleviated inflammation-induced barrier damage in vitro and in vivo. Bioinformatic analysis of UC patient datasets revealed an association between Piezo1 and zinc homeostasis and verified by elevated Piezo1 and ZnT1 expressions observed in both human UC and murine colitis samples. Suppression of Piezo1 led to ZnT1 downregulation in vitro and in vivo. Piezo1 activation caused enhanced Zn2+ efflux and intracellular Zn2+ depletion while Piezo1 inhibition led to Zn2+ accumulation. Effects of zinc supplementation and chelation were consistent with the view that ZnT1 inhibition alleviated barrier disintegration. Our findings revealed that Piezo1 affected ZnT1-mediated zinc homeostasis in IECs. Piezo1 suppression downregulated ZnT1 expression, attenuating intracellular zinc depletion caused by excessive Zn2+ efflux and relieved intestinal barrier disruption, indicating that Targeting the Piezo1-ZnT1-zinc signaling axis presents a promising therapeutic strategy for UC. Piezo1-activation exacerbates inflammation-induced intestinal barrier disruption by triggering Ca2+ influx which upregulates ZnT1-mediated Zn2+ efflux resulting in IECs Zn2+ dyshomeostasis, and this disruption can be rescued by Piezo1 suppression. The figure was generated by adobe illustrator.