Endogenous Neurotoxicity: A Pathophysiological Consequence of Homeostatic Dysfunction

Neurotoxicity is generally thought to result from exogenous agents like environmental chemicals, drugs and biological toxins. However, increasing evidence suggests that many endogenous molecules that play a critical role in normal brain function can become neurotoxic when the regulatory mechanism involved in their production, metabolism, compartmentalization and clearance are disrupted. This shift underlies the basis of endogenous neurotoxicity. This review discusses the major endogenous sources of neurotoxicity: metabolic neurotoxins, dysfunctional neurotransmitters, protein aggregates and inflammatory mediators. These endogenous factors arise from different physiological pathways, but share common pathogenic mechanisms, all of which involve an underlying state of oxidative stress, mitochondrial dysfunction, impaired proteostasis, excitotoxic signalling, neurovascular dysfunction and maladaptive neuroglial responses. This is not a singular process but a network of interconnected processes, which work together to progressively diminish neuronal resilience and promote synaptic dysfunction and neurodegeneration. The review also underscores the critical role of astrocytes, microglia and other glial cells in the maintenance of neuronal homeostasis. By integrating diverse endogenous neurotoxic pathways within a unified homeostasis-centred framework, this review provides a broader perspective on the mechanisms linking metabolic disorders, aging and neurodegenerative diseases. This framework suggests that effective therapeutic strategies may require restoration of physiological regulatory networks rather than targeting individual neurotoxic molecules in isolation. A systems-level understanding of endogenous neurotoxicity may therefore facilitate the development of earlier biomarkers and more effective interventions aimed at preserving neuronal homeostasis and preventing progressive neurological dysfunction.