Nan fang yi ke da xue xue bao = Journal of Southern Medical University · 2026
[miR-143-3p alleviates neuropathic pain in mice with spared nerve injury by targeting the KRAS/RalA pathway and inhibiting astrocyte activation].
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Lin Yixin, Yao Jinzhong, Chen Yeming, Qin Zaisheng
Аннотация
OBJECTIVES: To investigate the therapeutic effect of microRNA (miR-143-3p) on neuropathic pain in mice and clarify its target gene and molecular mechanism.
METHODS: Spared nerve injury (SNI) models were established in 8-week-old male C57BL/6J mice, with sham-operated mice as the control group (n=6). The treatment group received a single intrathecal injection of miR-143-3p agomir on day 7 after SNI modeling, and in KRAS agonist group, KRA-533 was intrathecally injected on day 8 following miR-143-3p agomir injection. Mechanical withdrawal thresholds of the ipsilateral paw of the mice were measured using von Frey filaments. Bioinformatics analyses were used to explore the potential targets and signaling pathways. In a C8-D1A astrocyte model of lipopolysaccharide (LPS)-induced inflammation, the effect of miR-143-3p mimic and KRA-533 on the expressions of the identified targets were detected using qRT-PCR and Western blotting. Spinal morphology in the mouse models and proliferative activity of C8-D1A cells were observed with immunofluorescence staining, and the levels of pro-inflammatory factors were determined with enzyme-linked immunosorbent assay (ELISA).
RESULTS: miR-143-3p agomir significantly increased mechanical withdrawal thresholds of SNI mice, and the effect lasted nearly 3 weeks. KRAS was identified as a direct target of miR-143-3p. In SNI mouse models, miR-143-3p significantly inhibited KRAS expression, RalA/TBK1/NF-κB signaling pathway activation, and astrocyte activation, and upregulated the levels of IL-6, IL-1β, and TNF-α. The KRAS agonist KRA-533 significantly reversed the analgesic effect of miR-143-3p and its inhibitory effects on downstream pathway activation, astrocyte activation, and neuroinflammation. In C8-D1A cells, overexpression of miR-143-3p effectively suppressed LPS-induced noncanonical Ras pathway activation and inhibited cell proliferation and inflammatory response, which were reversed by treatment with KRA-533.
CONCLUSIONS: miR-143-3p overexpression alleviates neuropathic pain in mice by targeting KRAS to regulate the noncanonical Ras pathway and inhibiting astrocyte activation and neuroinflammation, suggesting a new strategy for clinical treatment of SNI.
METHODS: Spared nerve injury (SNI) models were established in 8-week-old male C57BL/6J mice, with sham-operated mice as the control group (n=6). The treatment group received a single intrathecal injection of miR-143-3p agomir on day 7 after SNI modeling, and in KRAS agonist group, KRA-533 was intrathecally injected on day 8 following miR-143-3p agomir injection. Mechanical withdrawal thresholds of the ipsilateral paw of the mice were measured using von Frey filaments. Bioinformatics analyses were used to explore the potential targets and signaling pathways. In a C8-D1A astrocyte model of lipopolysaccharide (LPS)-induced inflammation, the effect of miR-143-3p mimic and KRA-533 on the expressions of the identified targets were detected using qRT-PCR and Western blotting. Spinal morphology in the mouse models and proliferative activity of C8-D1A cells were observed with immunofluorescence staining, and the levels of pro-inflammatory factors were determined with enzyme-linked immunosorbent assay (ELISA).
RESULTS: miR-143-3p agomir significantly increased mechanical withdrawal thresholds of SNI mice, and the effect lasted nearly 3 weeks. KRAS was identified as a direct target of miR-143-3p. In SNI mouse models, miR-143-3p significantly inhibited KRAS expression, RalA/TBK1/NF-κB signaling pathway activation, and astrocyte activation, and upregulated the levels of IL-6, IL-1β, and TNF-α. The KRAS agonist KRA-533 significantly reversed the analgesic effect of miR-143-3p and its inhibitory effects on downstream pathway activation, astrocyte activation, and neuroinflammation. In C8-D1A cells, overexpression of miR-143-3p effectively suppressed LPS-induced noncanonical Ras pathway activation and inhibited cell proliferation and inflammatory response, which were reversed by treatment with KRA-533.
CONCLUSIONS: miR-143-3p overexpression alleviates neuropathic pain in mice by targeting KRAS to regulate the noncanonical Ras pathway and inhibiting astrocyte activation and neuroinflammation, suggesting a new strategy for clinical treatment of SNI.