<p>Treatment-resistant depression (TRD), a clinically challenging issue of major depressive disorder (MDD), affects up to one-third of patients and is associated with elevated suicide risk and limited treatment options. Cumulative evidence highlights pathological microglial state and inflammasome-derived pyroptosis as key contributors to TRD pathophysiology. This study aimed to validate tomentosin as a network-based identified antidepressants and anti-microglial candidate and to define its mechanisms in suppressing microglial pyroptosis. Through a network-based multiscale interactome screening of a large terpenoid library exceeding 170,000 compounds, we identified tomentosin, a brain-penetrant sesquiterpene lactone with favorable drug-likeness and network relevance. In mice unresponsive to fluoxetine (called as FRD, fluoxetine-resistant depression), tomentosin (20 mg/kg) significantly alleviated depressive behaviors and normalized reactive microglial states in the anterior cingulate cortex (ACC). These pharmacological effects were observed in systemic and intracerebral inflammation-induced depressive mice models. We found that tomentosin mechanistically targeted the suppression of microglial NOD-like receptor protein-3 (NLRP3)/caspase-1/gasdermin D (GSDMD) signaling pathway. This inflammasome-specific suppressive effect was confirmed by the absence of pharmacological effects in caspase-1 knockout (Casp1 KO) mice. Underlying mechanisms were further validated through molecular interaction analyses, comparative studies with inhibitors, and overexpression vector transfections. Our findings suggest that tomentosin is a novel agent that selectively modulates inflammasome-associated microglia in FRD, primarily by suppressing pyroptosis in the ACC.</p>