Discovery of a Neuroprotective Diosgenin Derivative as a Novel Antidepressant Candidate Targeting LPS-TLR4 Signaling

Depression is a widespread and increasing mental disorder, yet current antidepressants, including tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs), often cause notable side effects and limited efficacy. Hence, safer therapeutic options are needed. Diosgenin, a phytosteroid sapogenin from the Dioscoreaceae plants, has demonstrated therapeutic potential for neurological disorders but is hindered by unclear target mechanism, poor solubility, and limited bioavailability. Here, we synthesized diosgenin derivatives and evaluated their biological activities. Among them, compound <b>8</b> exhibited the highest therapeutic index (TI = 19.8), strongly inhibiting LPS-induced NO production with minimal cytotoxicity. Compound <b>8</b> suppressed proinflammatory gene expression, showed neuroprotective effects <i>in vitro</i>, ameliorated LPS-induced reactive astrogliosis and microgliosis <i>in vivo</i>, and alleviated LPS-induced depressive-like behaviors in mice. Computational docking and centrifugal ultrafiltration assays identified LY96 as a potential target, suggesting modulation of LPS-TLR4 signaling. Collectively, these findings indicate that compound <b>8</b> holds promise as a safer antidepressant candidate.