Methamphetamine hijacks chaperone-mediated autophagy to degrade GPX4, driving ferroptosis-precipitated cognitive decline and addictive pathogenesis.

Abstract

Methamphetamine (METH) addiction is associated with progressive cognitive decline and maladaptive behaviors, but the molecular mechanisms bridging proteostatic dysfunction to neural circuit degeneration remain poorly defined. We hypothesized that METH hijacks chaperone-mediated autophagy (CMA), a lysosomal quality-control pathway, to drive neurodegeneration through ferroptosis. Using chronic METH self-administration models, hippocampal neurons, and CMA-targeted approaches, we demonstrated that METH coerces CMA components (HSC70-LAMP2A) to recognize a non-canonical ¹²⁴NVKFD¹²⁸ degron on glutathione peroxidase 4 (GPX4), resulting in its lysosomal degradation. This CMA-dependent GPX4 depletion disrupted glutathione recycling, unleashing lethal lipid peroxidation and hippocampal ferroptosis. Critically, neuronal CMA ablation rescued spatial memory deficits and reduced compulsive drug-seeking behaviors, establishing CMA hyperactivity as a causal driver of addiction-related neuropathology. Our findings extend the oxidative stress-centric model of METH toxicity by revealing CMA as a pathological switch that converts physiological proteostasis into a self-destructive cascade. The CMA-GPX4 axis, mechanistically linking protein quality control failure, iron-dependent cell death, and behavioral dysfunction, represents a druggable target, with CMA inhibitors showing preclinical efficacy in mitigating METH-induced neuropsychiatric deterioration. By redefining addiction-associated neurodegeneration as a disorder of hijacked proteostasis, this work provides a unified framework for targeting shared mechanisms in substance use disorders and neurodegenerative diseases.