Metformina activa AMPK para restringir la necropoptosis impulsada por ROS mitocondrial en la neurotoxicidad por...

Cadmium (Cd) exposure is an emerging risk factor for neurodegeneration, yet the contribution of necroptosis to Cd-induced neuronal loss and its tractability for pharmacologic intervention remain unclear. Here, we identify an AMP-activated protein kinase (AMPK)-mitochondrial reactive oxygen species (mtROS)-RIPK1/RIPK3-MLKL axis as a central driver of Cd neurotoxicity and a critical target of metformin. In a chronic Cd-exposed mouse model and in primary hippocampal neurons, Cd provoked prominent neuronal injury characterized by the activation of necroptotic signaling (elevated p-RIPK1, p-RIPK3, and p-MLKL), excessive mtROS production, and mitochondrial injury. Oral metformin preserved hippocampal neuronal integrity and suppressed necroptotic markers in vivo, while in cultured neurons and SH-SY5Y cells, it reduced mtROS, maintained mitochondrial morphology and membrane potential, and prevented necrosome assembly. Pharmacologic inhibition of RIPK1 (necrostatin-1) or RIPK3 (GSK-872), as well as CRISPR/Cas9-mediated deletion of RIPK1, RIPK3, or MLKL, attenuated Cd-induced necrosis and phenocopied or enhanced the anti-necroptotic effects of metformin. Mechanistically, metformin restored Cd-suppressed AMPK activity, whereas blockade of AMPK with compound C or expression of a dominant-negative AMPKα1 mutant abolished metformin-mediated suppression of mtROS, RIPK1/RIPK3-MLKL signaling, and necroptosis. Scavenging mtROS with Mito-TEMPO or MitoQ reduced necroptosis and synergized with metformin to disrupt RIPK3-MLKL complex formation. Collectively, these findings demonstrate that Cd triggers neuronal necroptosis via mtROS-driven activation of RIPK1/RIPK3-MLKL, and that metformin confers neuroprotection by activating AMPK to restore mitochondrial homeostasis and restrain necroptotic signaling. This work positions the AMPK-mtROS-necroptosis axis as a therapeutically actionable pathway in heavy-metal neurotoxicity and supports repurposing metformin for necroptosis-associated neurodegenerative conditions.