Discovery of Zharp1-163 as a dual inhibitor of ferroptosis and necroptosis for the treatment of inflammatory disorders and kidney injury.

Dysregulation of cell death plays a critical role in the onset and progression of numerous human diseases. Distinct forms of regulated cell death, such as necroptosis and ferroptosis, have been implicated in the pathogenesis of various conditions, including neurodegenerative disorders and acute kidney injury. Strategies that concurrently target both necroptosis and ferroptosis present significant potential for improving therapeutic outcomes. In this study, we identified Zharp1-163 as a dual inhibitor of ferroptosis and necroptosis in both human and mouse species. Zharp1-163 effectively blocks ferroptosis by reducing reactive oxygen species (ROS) levels and inhibits necroptosis by potently and selectively targeting RIPK1 kinase activity. In vivo, Zharp1-163 markedly attenuated TNF-α-induced systemic inflammatory syndrome, including the prevention of TNF-α-induced mortality and hypothermia in mice. Notably, Zharp1-163 significantly alleviated acute kidney injury associated with both necroptosis and ferroptosis in models induced by cisplatin treatment and ischemia-reperfusion. Collectively, our findings establish Zharp1-163 as a dual-action inhibitor capable of effectively suppressing both ferroptosis and necroptosis. These findings highlight its great potential in the treatment of diseases associated with these cell death pathways, such as kidney disease.