{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T06:10:09Z","timestamp":1790143809392,"version":"4.0.1"},"reference-count":38,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T00:00:00Z","timestamp":1790121600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Lumbar radicular pain (LRP) is a prevalent neuropathic pain disorder driven by nucleus pulposus (NP)-induced inflammation. Protectin DX (PDX), a novel specialized pro-resolving lipid mediator (SPM), exerts pro-resolving and analgesic effects in LRP. However, the underlying molecular mechanisms remain unclear. Emerging evidence suggests that crosstalk between necroptosis and autophagy coordinately regulates cell fate and inflammatory responses. This study therefore investigated whether this crosstalk mediates the therapeutic effects of PDX in LRP.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Rat models of LRP were established by transplanting autologous NP onto the L5 dorsal root ganglion. The rats received intrathecal injections of PDX (10, 100, or 200\u00a0ng), GSK'872 (a receptor-interacting protein kinase 3 (RIP3) inhibitor), chloroquine (CQ; an autophagy inhibitor), or Compound C (an adenosine monophosphate-activated protein kinase (AMPK) inhibitor). Mechanical withdrawal threshold and thermal withdrawal latency were measured. Necroptosis-associated markers (RIP3 and mixed lineage kinase domain-like protein (MLKL)), autophagy markers (microtubule-associated protein 1A\/1B light chain 3B and sequestosome 1), AMPK signaling molecules, and proinflammatory cytokines (interleukin-1\u03b2, interleukin-6, and tumor necrosis factor-\u03b1) were assessed by Western blotting and immunofluorescence staining. Necrotic cells were detected by propidium iodide (PI) staining.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>NP transplantation induced persistent pain hypersensitivity, decreased AMPK phosphorylation, impaired autophagic function, upregulated RIP3 and MLKL expression, increased the number of PI-positive cells, and elevated pro-inflammatory cytokine levels in the lumbar spinal cord of LRP rat models. Intrathecal administration of PDX dose-dependently attenuated pain hypersensitivity, restored AMPK phosphorylation and autophagic function, and suppressed spinal RIP3\/MLKL-associated necroinflammation. These beneficial effects were significantly reversed by pretreatment with either CQ or Compound C.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>PDX alleviates LRP by restoring AMPK-related autophagic function, thereby suppressing RIP3\/MLKL-associated necroinflammation. These findings support PDX as a potential therapeutic candidate for experimental LRP and provide mechanistic insight into the role of SPMs in experimental pain regulation.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1957244","type":"journal-article","created":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T05:49:22Z","timestamp":1790142562000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Protectin DX alleviates lumbar radicular pain in rats by suppressing RIP3\/MLKL-associated necroinflammation through restoration of autophagic function"],"prefix":"10.3389","volume":"17","author":[{"given":"Qing-xiang","family":"Zhao","sequence":"first","affiliation":[{"name":"Department of Pain Management, Shandong Medical and Pharmaceutical University Hospital","place":["Binzhou, Shandong Province, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao-juan","family":"Wu","sequence":"additional","affiliation":[{"name":"College of Public Health, Shandong Second Medical University","place":["Weifang, Shandong Province, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qing","family":"Yao","sequence":"additional","affiliation":[{"name":"Department of Pain Management, Shandong Medical and Pharmaceutical University Hospital","place":["Binzhou, Shandong Province, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Pain Management, Shandong Medical and Pharmaceutical University Hospital","place":["Binzhou, Shandong Province, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,23]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"101733","DOI":"10.1016\/j.mtbio.2025.101733","article-title":"Inflammation resolution-based treatment of atherosclerosis using biomimetic nanocarriers loaded with specialized pro-resolving lipid mediators","volume":"32","author":"Anghelache","year":"2025","journal-title":"Mat. 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