INPP5D Upregulation by Minocycline Mitigates Sepsis-Associated Neuroinflammation and Neuronal Dysfunction Via Microglial Autophagy and Antioxidant Pathways

Sepsis-associated neuroinflammation contributes to long-term neurological deficits, but therapeutic strategies remain limited. Here, we demonstrate that minocycline (Mino) mitigates sepsis-induced neuroinjury by upregulating inositol polyphosphate-5-phosphatase D (INPP5D), thereby suppressing microglia-mediated central amygdala (CeA) neuronal hyperactivation. In a cecal ligation and puncture (CLP)-induced septic mouse model, Mino treatment improved behavioral deficits and reduced neuroinflammation. Multi-omics analyses identified INPP5D as a critical downstream effector of Mino's neuroprotection. In vitro, Mino enhanced INPP5D expression in microglia, concurrently inhibiting pro-inflammatory activation, promoting autophagy, restoring mitochondrial function, and augmenting antioxidant responses. Microglia-neuron co-culture experiments revealed that Mino-dependent INPP5D upregulation attenuated CeA neuronal hyperexcitability and dendritic spine loss. Crucially, in vivo silencing of INPP5D or autophagy blockade abolished Mino's protective effects, confirming the INPP5D-autophagy axis as indispensable for neuroprotection. Our findings unveil a novel mechanism whereby Mino rescues sepsis-induced neuroinjury via INPP5D-mediated modulation of microglial activation and CeA neuronal dysfunction, offering a promising therapeutic target for sepsis-associated encephalopathy.