{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T09:15:06Z","timestamp":1783674906052,"version":"3.55.0"},"reference-count":71,"publisher":"Wiley","issue":"16","license":[{"start":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T00:00:00Z","timestamp":1779148800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T00:00:00Z","timestamp":1779148800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["LCZBYJYZZ2024\u2010003"],"award-info":[{"award-number":["LCZBYJYZZ2024\u2010003"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[2026,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background and Purpose<\/jats:title>\n                    <jats:p>Knee osteoarthritis (KOA) is a degenerative joint disease characterised by chronic pain. This study investigated the effects of casticin on KOA\u2010associated cold hyperalgesia and its underlying mechanisms.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Experimental Approach<\/jats:title>\n                    <jats:p>KOA was induced in C57BL\/6J mice using the destabilisation of the medial meniscus (DMM) model. Cold hyperalgesia was assessed through cold plate and acetone tests. Interleukin\u20104 was used to induce M2 macrophage polarisation, whereas dupilumab was employed to inhibit M2 activation. Casticin treatment was administered to evaluate its effects on SET domain bifurcated histone\u2010lysine methyltransferase 2 (SETDB2) expression, macrophage polarisation, dorsal root ganglion neuronal autophagy, and mitochondrial function. shRNA\u2010mediated SETDB2 knockdown was performed to confirm its role in KOA pain modulation. Western blotting, quantitative real\u2010time PCR (qPCR), immunofluorescence and enzyme\u2010linked immunosorbent assays (ELISA) were used to analyse macrophage polarisation and autophagy markers, mitochondrial function and mitochondrial membrane potential [MMP], and pain mediators.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key Results<\/jats:title>\n                    <jats:p>M2 macrophage polarisation enhanced neuronal autophagy, by increasing LC3B, P62 and Beclin1 expression, and improved mitochondrial function by reducing ROS accumulation, restoring ATP production and increasing MMP levels. These changes correlated with reduced cold hyperalgesia and decreased expression of nociceptive markers (CGRP and TRPA1). Casticin treatment further promoted M2 macrophage polarisation, enhanced neuronal autophagy, and restored mitochondrial function, leading to significant pain relief. SETDB2 knockdown partially reversed these effects, confirming its essential role in M2\u2010driven autophagy activation and pain modulation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions and Implications<\/jats:title>\n                    <jats:p>Casticin alleviated KOA\u2010induced cold hyperalgesia by up\u2010regulating SETDB2, promoting M2 macrophage polarisation, enhancing neuronal autophagy, and restoring mitochondrial function.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/bph.70512","type":"journal-article","created":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T04:46:44Z","timestamp":1779252404000},"page":"5033-5061","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Casticin promotes M2 macrophage polarisation and dorsal root ganglion neuronal autophagy to alleviate cold hyperalgesia in knee osteoarthritis by regulating histone\u2010lysine N\u2010methyltransferase (SETDB2)"],"prefix":"10.1111","volume":"183","author":[{"given":"Yibao","family":"Wei","sequence":"first","affiliation":[{"name":"Department of Orthopedics and Traumatology Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Provincial Hospital of Traditional Chinese Medicine  Nanjing China"},{"name":"Key Laboratory for Metabolic Diseases in Chinese Medicine Nanjing University of Chinese Medicine  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Songjiang","family":"Yin","sequence":"additional","affiliation":[{"name":"Department of Orthopedics and Traumatology Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Provincial Hospital of Traditional Chinese Medicine  Nanjing China"},{"name":"Key Laboratory for Metabolic Diseases in Chinese Medicine Nanjing University of Chinese Medicine  Nanjing 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Chinese Medicine, Jiangsu Provincial Hospital of Traditional Chinese Medicine  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taiyang","family":"Liao","sequence":"additional","affiliation":[{"name":"Key Laboratory for Metabolic Diseases in Chinese Medicine Nanjing University of Chinese Medicine  Nanjing China"},{"name":"Department of Orthopedics and Traumatology The Second Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Second Chinese Medicine Hospital  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peimin","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Orthopedics and Traumatology Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Provincial Hospital of Traditional Chinese Medicine  Nanjing China"},{"name":"Nanjing University of Chinese Medicine Clinical Research Institute for Knee Osteoarthritis  Nanjing 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