Pham, Thuy Linh Sharma, Ramesh Neupane, Chiranjivi Gao, Feifei Cha, Guang-Ho Kim, Hyunjin Nam, Min-Ho Lee, Seung Eun Yang, Sunjung Sim, Hunju Lee, Sanghoon Hur, Gang Min Kim, Hyun-Woo Park, Jin Bong 2025-09-04T05:00:06Z 2025-09-04T05:00:06Z 2025-09-04 2025-09 0304-3959 https://pubs.kist.re.kr/handle/201004/153119 Stimulator of interferon genes (STING), a pivotal immune regulator, has emerged as a contributor to nociception, yet its role in chronic pains remains still unknown. Here, we demonstrate that STING plays a dual role in normal and neuropathic pain in mature male rodents. Stimulator of interferon genes maintains type I interferon (IFN-I) level restraining pain sensitivity in normal and sham control, while activated STING/interferon regulatory factor 3 (IRF3) signaling increases the expression of gamma-aminobutyric acid (GABA) transporter 1 (GAT1) in the spinal cord (SC), thus, generating paclitaxel (PTX)-induced peripheral neuropathy. Genetic interference of STING (STING(-/-) mice) attenuated PTX-induced mechanical hypersensitivity with attenuated PTX-induced GAT1 increase, preventing PTX-induced increase in tonic GABA(A) inhibition of the spinal dorsal horn neurons. Stimulator of interferon genes regulates GAT expression through a TANK-binding kinase 1 (TBK1)-IRF3 signaling pathway, with IRF3 as a crucial transcription factor. Silencing neuronal STING, as opposed to its astrocytic counterpart, effectively restrained the PTX-induced mechanical hypersensitivity and GAT1 increase in the SC. Pharmacological inhibition of STING (H-151) efficiently diminished the TBK1/IRF3/GAT1 signaling pathway to alleviate PTX-induced mechanical hypersensitivity. Our findings show that STING-IRF3 serves a dual role: suppressing physiological nociception through IFN-I and acting as a transcriptional regulator of GAT1, contributing to chemotherapy-induced neuropathic pain. English Wolters Kluwer Health Neuronal STING-GAT1 signaling maintains paclitaxel-induced neuropathic pain in the spinal cord Article 10.1097/j.pain.0000000000003593 1 Pain, v.166, no.9, pp.e288 - e302 Pain 166 9 e288 e302 Y scie scopus 001555106500001 2-s2.0-105004311189 Anesthesiology Clinical Neurology Neurosciences Anesthesiology Neurosciences & Neurology Article GABA-TRANSPORTER GAT-1 DORSAL-HORN NERVE LIGATION UP-REGULATION ACTIVATION EXPRESSION MODEL ASTROCYTES MICROGLIA PROTEIN STING-IRF3 pathway GABA transporters GABA(A) inhibition Peripheral neuropathy