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Here we demonstrate the analgesic actions of PDX in a mouse model of tibial fracture-induced postoperative pain (fPOP) via activation of GPR37. Intravenous early-phase and late-phase treatment of PDX (100 ng\/mouse) effectively alleviated fPOP. Compared to protectin D1\/neuroprotectin D1, DHA, steroid, and meloxicam, PDX produced superior pain relief. While dexamethasone and meloxicam prolonged fPOP, PDX shortened the pain duration. The analgesic effects of PDX were abrogated in\n                  <jats:italic>Gpr37<\/jats:italic>\n                  <jats:sup>\u2212\/\u2212<\/jats:sup>\n                  mice, which displayed deficits in fPOP resolution. PDX binds GPR37 and induces calcium responses in peritoneal macrophages. LC-MS-MS-based lipidomic analysis revealed that endogenous PDX levels were \u223c10-fold higher than PD1 in muscle at the fracture site. PDX promotes macrophage polarization via GPR37-dependent phagocytosis and efferocytosis through calcium signaling\n                  <jats:italic>in vitro<\/jats:italic>\n                  , and it further enhances macrophage viability and efferocytosis\n                  <jats:italic>in vivo<\/jats:italic>\n                  via GPR37. Finally, PDX rapidly modulates nociceptor neuron responses by suppressing C-fiber-induced muscle reflex\n                  <jats:italic>in vivo<\/jats:italic>\n                  and calcium responses in DRG neurons\n                  <jats:italic>ex vivo<\/jats:italic>\n                  and reducing TRPA1\/TRPV1-induced acute pain and neurogenic inflammation\n                  <jats:italic>in vivo<\/jats:italic>\n                  . Our findings highlight multiple benefits of PDX to manage postoperative pain and promote perioperative recovery.\n                <\/jats:p>","DOI":"10.1101\/2025.11.10.687700","type":"posted-content","created":{"date-parts":[[2025,11,12]],"date-time":"2025-11-12T20:20:15Z","timestamp":1762978815000},"source":"Crossref","is-referenced-by-count":1,"title":["Protectin DX resolves fracture-induced postoperative pain in mice via neuronal signaling and GPR37-activated macrophage efferocytosis"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3810-2689","authenticated-orcid":false,"given":"Yize","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9092-0075","authenticated-orcid":false,"given":"Sangsu","family":"Bang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-3919-4503","authenticated-orcid":false,"given":"Jasmine","family":"Ji","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sharat","family":"Chandra","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4627-8545","authenticated-orcid":false,"given":"Charles N","family":"Serhan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9355-3688","authenticated-orcid":false,"given":"Ru-Rong","family":"Ji","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025111401300462000_2025.11.10.687700v1.1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2015.09.036"},{"key":"2025111401300462000_2025.11.10.687700v1.2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1614017113"},{"key":"2025111401300462000_2025.11.10.687700v1.3","doi-asserted-by":"crossref","unstructured":"Aldanyowi SN . 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