Gut microbiota-derived indole-3-propionic acid attenuates Arsenic trioxide-induced cognitive impairment by inhibiting ubiquitination and degradation of BRD4.

BACKGROUND AND PURPOSE: Arsenic trioxide (ATO) therapy for acute promyelocytic leukaemia (APL) can induce neurological disorders, including cognitive impairment (CI) and depression, severely impacting patient quality of life, yet effective interventions are lacking. Clinical observations indicate ATO treatment is associated with gut microbiota dysbiosis. Given the crucial role of gut microbes and their metabolites in neurological health, this study investigated indole-3-propionic acid (IPA), a neuroprotective microbiota-derived metabolite capable of crossing the blood-brain barrier. RESULTS: In ATO-treated mice, behavioural tests confirmed significant cognitive decline. 16S rRNA genotyping revealed a reduction in Bifidobacterium abundance, and metabolomics identified a concomitant decrease in its metabolite, IPA, alongside disruptions in the tricarboxylic acid cycle and glycolysis. IPA supplementation alleviated ATO-induced intestinal inflammation and behavioural deficits. Mechanistically, IPA inhibited ATO-induced BRD4 degradation and the associated reduction in H4 acetylation, thereby restoring the expression of the metabolic enzyme PFKM and the synaptic protein PSD95. CONCLUSION: IPA mitigates ATO-induced intestinal injury and glycolytic dysfunction via the 'BRD4-H4ac-PFKM' axis, providing novel insights for preventing and treating ATO-induced neurotoxicity.