Sodium Houttuyfonate improves cognitive impairment in mice after chronic sleep deprivation by inhibiting microglial inflammation and ferroptosis.

Chronic sleep deprivation (CSD) impairs hippocampal function and induces learning and memory deficits. Microglia-driven neuroinflammation and ferroptosis are implicated in CSD-associated hippocampal pathology, yet targeted pharmacological interventions remain limited. Here, we evaluated whether Sodium Houttuyfonate (SH) ameliorates CSD-related cognitive impairment and explored the underlying mechanisms. We used network pharmacology to predict SH targets and pathways in CSD, which were validated in CSD mice and in LPS- and Erastin-treated BV-2 microglia. Network pharmacology analysis identified multiple putative key targets shared between SH and CSD, with enrichment predominantly in inflammation-related signaling pathways. In CSD mice, SH improved cognitive performance and attenuated tissue damage in the hippocampal CA1, CA3, and DG regions. Concurrently, it suppressed hippocampal microglial activation, attenuated the inflammatory response, and alleviated CSD-induced ferroptosis-related alterations. In vitro, SH reversed LPS-induced inflammatory responses in BV-2 cells by modulating the SOCS3/STAT3 pathway, and si-SOCS3 treatment significantly diminished these anti-inflammatory effects of SH, confirming that SH's regulation of microglial inflammation is SOCS3-dependent. In an Erastin-induced ferroptosis model in BV-2 cells, SH restored the function of the classical ferroptosis regulators SLC7A11 and GPX4, as well as additional key ferroptosis-related proteins FTH1 and ACSL4, thereby ameliorating the ferroptosis phenotype. In summary, SH ameliorates CSD-associated cognitive impairment and mitigates hippocampal damage. Its mechanism may involve SOCS3/STAT3-mediated anti-inflammatory effects and regulation of multiple ferroptosis-associated proteins, including both classical regulators and additional key proteins, thereby suppressing microglia-mediated neuroinflammation and ferroptosis. This provides experimental support and new research directions for intervention strategies targeting CSD-related cognitive impairment.