Aims <p>This study aimed to investigate the neurological and behavioural effects of exposure to the environmental endocrine disruptor 17β-trenbolone (17-TB) exposure in chronic social defeat stress (CSDS)-induced mice and elucidate the role of lipocalin 2 (LCN2) in linking peripheral inflammation to neurodegeneration.</p> Methods and Materials <p>Male BALB/c mice were subjected to the CSDS paradigm and treated with 17-TB (100&#xa0;μg/kg) or vehicle control for 10 consecutive days. Behavioural assessments, including novel object recognition test, novel object location test and social interaction test, were conducted to evaluate cognitive memory and social behaviour. Western blotting, ELISA and immunofluorescence were used to analyse LCN2 expression and related inflammatory markers in the liver and brain.</p> Results <p>The results showed that 17-TB exposure exacerbated the induction of serum TNF-α and IL-1β inflammation in CSDS-induced mice, leading to activation of the hepatic IL-6 inflammatory factor pathway. This enhanced the release of hepatic LCN2 and stimulated its expression in the medial prefrontal cortex (mPFC) via the peripheral circulation, which subsequently activated the dorsal motor vagal nucleus (DMX) through cholinergic neuron (ChAT⁺) hyperactivation and c-Fos⁺ upregulation. This neurovisceral circuit ultimately induces hippocampal and cortical amyloid-β (Aβ) deposition, leading to cognitive memory and social deficits, thereby inducing Alzheimer’s disease (AD)-like pathological changes.</p> Conclusion <p>This study highlights the critical role of the brain–liver axis in inducing LCN2 release and ultimately cognitive deficits similar to AD-like symptoms in a 17-TB-exposed CSDS-induced mouse model, highlighting the risk of environmental endocrine disruptors causing neurodegenerative diseases that require further investigations and safety assessments.</p>