Geniposide attenuates astrocyte pyroptosis in depression via long non‐coding RNA Six3os1‐mediated regulation of the miR‐511‐3p/COL9A3 axis and MAPK/NLRP3 signaling

Depression involves multifaceted molecular pathways, with astrocyte pyroptosis emerging as a critical contributor to neuroinflammation. This study reveals that geniposide, a natural compound, alleviates depressive-like behaviors in chronic unpredictable mild stress mice by targeting a long non-coding RNA (lncRNA)-mediated signaling axis. Bioinformatics analysis identified Six3os1 as a key lncRNA sponging miR-511-3p, thereby upregulating COL9A3 and suppressing the MAPK/NLRP3 pathway. Behavioral tests (sucrose preference, tail suspension, and Morris water maze) demonstrated that geniposide (100 mg/kg) reversed CUMS-induced depressive behaviors. Histological and molecular analyses confirmed geniposide's ability to restore hippocampal integrity, reduce astrocyte pyroptosis, and downregulate pyroptosis markers (ASC, cleaved Casp-1, GSDMD-N, and IL-1β). Dual-luciferase and RNA pull-down assays validated the Six3os1/miR-511-3p/COL9A3 interaction, whereas Western blotting showed geniposide inhibited MAPK phosphorylation (p-p38, p-ERK1/2) and NLRP3 activation. Overexpression of Six3os1 or silencing of miR-511-3p mimicked geniposide's effects, whereas COL9A3 knockdown exacerbated pyroptosis. These findings establish a novel ceRNA mechanism wherein geniposide modulates astrocyte survival via Six3os1-dependent regulation of miR-511-3p and MAPK/NLRP3 signaling, offering therapeutic insights for depression.