{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T12:16:50Z","timestamp":1791289010594,"version":"4.3.0"},"reference-count":65,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,5,13]],"date-time":"2025-05-13T00:00:00Z","timestamp":1747094400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["\u7f16\u53f7 81971152"],"award-info":[{"award-number":["\u7f16\u53f7 81971152"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Microglia polarization is crucial in mediating neuropathic pain. However, the role of microglia polarization in regulating spinal cord ischemia-reperfusion injury (SCIRI)-induced neuropathic pain is largely unknown. This study aimed to elucidate the relationship between SCIRI-induced neuropathic pain and microglia polarization, as well as the underlying mechanisms, with the objective of identifying potential therapeutic targets.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      A rat model of SCIRI was established by aortic arch clamping, then pain thresholds were measured.\n                      <jats:italic>In vitro<\/jats:italic>\n                      , oxygen-glucose deprivation\/reperfusion (OGD\/R) of HAPI microglia was performed. The expressions of sirtuin1 (SIRT1), SMAD specific E3 ubiquitin protein ligase 2 (SMURF2), and markers of microglial polarization (CD206, iNOS) were quantitated by Western blot and immunofluorescence, and the levels of cytokines (TNF-\u03b1, IL-4) were assessed by Enzyme-linked immunosorbent assay (ELISA). Real-time quantitative reverse transcription PCR (RT-qPCR) experiments were conducted to quantify the levels of miR-148a-3p and FOXA2. Dual-luciferase reporter assay was employed to identify the targeted regulation of SMURF2 by miR-148a-3p and the transcriptional regulation of miR-148a-3p by FOXA2. The regulatory role of FOXA2 in the transcription of miR-148a-3p was validated using chromatin immunoprecipitation (ChIP). In addition, co-immunoprecipitation (Co-IP) assays were performed to confirm the binding relationship between SMURF2 and FOXA2. And the ubiquitination levels of FOXA2 and SIRT1 were measured. Subsequently, rats were administered miR-148a-3p to assess pain thresholds. Western blot and immunofluorescence quantitative analysis was conducted to assess the expression of markers associated with microglia polarization.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      SCIRI significantly reduced mechanical and thermal pain thresholds in rats and promoted microglial polarization, with a concomitant decrease in SIRT1 expression and an increase in SMURF2 expression in microglial cells. Further analysis revealed that upregulation of miR-148a-3p promoted microglia polarization toward M2 by targeting SMURF2, which in turn inhibited ubiquitination of SIRT1. FOXA2 was an upstream transcription factor of miR-148a-3p and SMURF2 bound to FOXA2, resulting in its ubiquitination. Finally,\n                      <jats:italic>in vivo<\/jats:italic>\n                      experiments demonstrated that miR-148a-3p effectively promoted microglia transformation from M1 to M2 and reduced neuropathic pain following SCIRI.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>The FOXA2\/miR-148a-3p\/SMURF2 signaling feed-forward loop regulates SIRT1 levels and thereby exerts control over microglia polarization and the regulation of SCIRI-induced neuropathic pain.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2025.1563377","type":"journal-article","created":{"date-parts":[[2025,5,13]],"date-time":"2025-05-13T11:56:43Z","timestamp":1747137403000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":7,"title":["FOXA2\/miR-148a-3p\/SMURF2 signaling feed-forward loop alleviates spinal cord ischemia-reperfusion injury-induced neuropathic pain by modulating microglia polarization in 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