Hydrogen inhibits endometrial cancer growth via a ROS/NLRP3/caspase-1/GSDMD-mediated pyroptotic pathway.

Abstract

This study examined whether hydrogen could induce pyroptosis in endometrial cancer cells via a ROS-dependent inflammasome pathway. Immunohistochemical and western blot analyses confirmed elevated expression of NLRP3, caspase-1, and GSDMD in human endometrial cancer specimens and derived cell lines. Hydrogen pretreatment elevated intracellular and mitochondrial ROS levels, upregulated pyroptosis-associated proteins, increased PI- and TUNEL-positive cell counts, and enhanced LDH and IL-1β release. Knockdown of GSDMD using shRNA lentivirus attenuated these effects, confirming GSDMD's functional role. In a xenograft mouse model, hydrogen-rich water administration significantly reduced tumor volume and weight, with tumor sections showing moderate-to-strong NLRP3, caspase-1, and GSDMD positivity. These findings indicate that hydrogen activates the NLRP3 inflammasome/GSDMD axis to drive pyroptotic cell death in endometrial cancer.

Mechanism

Hydrogen elevates intracellular and mitochondrial ROS, activating the NLRP3 inflammasome. Subsequent caspase-1 cleavage of GSDMD triggers pyroptotic cell death in endometrial cancer cells, reducing tumor growth in vivo.