Estrogen's master switch: NFκB-NLRP3, SIRT1-HMGB1, and TLR4 triad tamed for brain rescue in ageing and neurodegeneration.

Estrogen operates as a pleiotropic steroidal, neuroendocrine modulator to combat accelerated brain ageing and neurodegeneration by addressing a convergent inflammatory-metabolic trio. Estrogen receptor-dependent neural cellular signalling reduces TLR4-mediated immune priming and NF-κB activation, preventing NLRP3 inflammasome assembly and pro-inflammatory cytokine release. Concurrently, estrogen increases SIRT1 activity, restoring metabolic and epigenetic equilibrium while inhibiting HMGB1 acetylation, translocation, extracellular release, and activation of the stress-response pathway. Coordinated regulation of the TLR4-NFκB-NLRP3 and SIRT1-HMGB1 molecular triad reduces chronic neuroinflammation, preserves neuronal integrity, metabolic resilience, and slows persistent inflammation-driven brain ageing. This highlights estrogen and estrogen-based steroidal modulators as promising therapeutic candidates for reversing accelerated cognitive ageing and neurodegenerative disorders. However, a crucial research gap persists in the absence of a systems-level assessment of neurosteroids as a multi-target regulator of convergent innate immunological and metabolic signalling networks. The control of the TLR4-NFκB-NLRP3 inflammasome axis and the SIRT1-HMGB1 metabolic-epigenetic checkpoint has not been well studied as an interrelated, steroidal druggable trifecta driving brain homeostasis and neurodegeneration. These pathways are often studied in isolation, despite overwhelming evidence that their bidirectional interplay contributes to persistent neuroinflammation, immunometabolic dysfunction, and cellular senescence. This review synthesises evidence from molecular endocrinology, biochemical, pre-clinical, and clinical models to advance a mechanistically integrated and therapeutically actionable framework that aligns into a unified endocrine, metabolic, and immune target-driven framework relevant to complex, inflammation-driven brain ageing, thereby offering a strong foundation and paving the way for future molecular target validation and disease-modifying, steroid-mimetic interventions against neurodegeneration.