Chlorogenic acid attenuates TBI-induced neuroinflammation by suppressing cGAS-STING signaling.

Traumatic brain injury (TBI) induces persistent neuroinflammation that contributes to secondary brain injury and neurological dysfunction. The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway is a key regulator of post-traumatic innate immune responses. Although chlorogenic acid (CGA) possesses well-established anti-inflammatory properties, the mechanisms underlying its protective effects after TBI remain incompletely understood. CGA efficacy was evaluated using a murine controlled cortical impact model. Bulk and single-cell RNA sequencing, network pharmacology, and mouse-specific molecular docking simulations were combined to identify candidate pathways. The underlying mechanism was further investigated in vivo and in LPS-stimulated BV2 microglia using the STING agonist DMXAA. CGA treatment significantly improved neurological function, enhanced cognitive performance, and alleviated blood-brain barrier disruption after TBI. Integrated analyses implicated cGAS-STING signaling as a candidate pathway associated with CGA action, with single-cell transcriptomic analysis showing relatively high pathway activity in microglia and infiltrating myeloid populations. Mechanistically, CGA reduced cGAS expression, inhibited the phosphorylation of STING, TBK1, and IRF3, and decreased pro-inflammatory cytokine production in vivo. In vitro, CGA decreased the expression of inflammatory and interferon-stimulated genes in a concentration-dependent manner and reduced reactive oxygen species accumulation; these effects were largely reversed by DMXAA. CGA attenuates neuroinflammatory responses and improves neurological outcomes after TBI, with early suppression of cGAS-STING signaling potentially contributing to these effects. These findings support further investigation of cGAS-STING signaling as a potential therapeutic target in TBI.