Tauopathies encompass a diverse group of neurodegenerative disorders characterized by abnormal TAU accumulation, synaptic dysfunction, neuroinflammation, and progressive neuronal loss. Beyond its role as a pathological hallmark, increasing evidence indicates that TAU actively drives neurodegeneration by disrupting mitochondrial function, promoting oxidative stress, and triggering maladaptive innate immune responses. In this context, pyroptosis, a highly inflammatory form of programmed cell death mediated by inflammasome activation and GASDERMIN pore formation, has emerged as a critical mechanism linking TAU pathology to chronic neuroinflammation and neuronal damage. This review summarizes current advances on the molecular crosstalk between TAU pathology, redox imbalance, inflammasome signaling, and pyroptotic cell death across primary and secondary tauopathies, including Alzheimer’s disease (AD) and frontotemporal lobar degeneration (FTLD). We discuss how pathological TAU induces mitochondrial dysfunction and reactive oxygen species generation, providing key priming and activation signals for inflammasomes, particularly NLRP3, in microglia and other brain cells. Pyroptosis is highlighted as a downstream effector that amplifies neuroinflammation through the release of pro-inflammatory cytokines and danger-associated molecular patterns, thereby sustaining TAU propagation and neurodegeneration. Special attention is paid to the redox-sensitive transcription factor NRF2 as a central regulatory node capable of counteracting oxidative stress, inflammasome activation, and pyroptosis. Finally, we examine emerging therapeutic strategies targeting pyroptotic and redox pathways, discussing their translational potential and current limitations. Overall, this review positions pyroptosis-driven redox-immune dysregulation as a promising yet underexplored therapeutic target in TAU-driven neurodegenerative diseases. • TAU pathology, oxidative stress, and neuroinflammation form a self-reinforcing pathogenic loop • Pyroptosis emerges as a key inflammatory cell-death mechanism linking TAU and NLRP3 inflammasome activation • NRF2 is a central regulatory node counteracting oxidative stress, inflammasome activation, and pyroptosis • Targeting pyroptosis and redox pathways represents a promising therapeutic strategy for tauopathies • Challenges remain for clinical translation due to co-pathology, BBB limitations, and incomplete mechanistic clarity
López et al. (Wed,) studied this question.