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.