Molybdenum and cadmium co-induced apoptosis and necroptosis via activating endoplasmic reticulum stress and upregulating Caspase-8 expression in duck hepatocytes

Hepatic diseases present a significant global public health challenge, with cadmium (Cd) and excess molybdenum (Mo) were identified as major environmental toxicants contributing to liver injury. Nevertheless, their precise mechanistic pathways remain incompletely understood. Hence, the hepatotoxicity mechanisms of Mo and Cd were roundly analyzed by network toxicology in this research, the analysis confirmed that these metals primarily induce liver injury through endoplasmic reticulum (ER) stress, apoptosis and necroptosis. Experimental validation further demonstrated that Cd and Mo jointly induce ER stress-mediated apoptosis and necroptosis in duck hepatocytes, and Caspase-8 restrains necroptosis via cleaving RIPK1 and mediates RIPK1-dependent apoptosis, suggesting Caspase-8-mediated proteolytic cleavage of RIPK1 acts as a critical regulatory switch between these two modes of programmed cell death. This investigation additionally elucidated the hepatotoxic mechanisms of Cd and Mo in poultry, and established an academic basis for developing therapeutic interventions against liver pathologies induced by Mo and Cd.