{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T02:42:34Z","timestamp":1790390554632,"version":"4.1.0"},"reference-count":40,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T00:00:00Z","timestamp":1777593600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T00:00:00Z","timestamp":1777593600000},"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":["32130060"],"award-info":[{"award-number":["32130060"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82401633"],"award-info":[{"award-number":["82401633"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82072160"],"award-info":[{"award-number":["82072160"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004608","name":"Natural Science Foundation of Jiangsu Province","doi-asserted-by":"publisher","award":["BK20232023"],"award-info":[{"award-number":["BK20232023"]}],"id":[{"id":"10.13039\/501100004608","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J cachexia sarcopenia muscle"],"published-print":{"date-parts":[[2026,6]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Peripheral nerve injury\u2010induced muscle atrophy shares core pathophysiological features with systemic wasting disorders including cachexia and sarcopenia, yet early molecular triggers remain undefined. This study investigates the pathogenic role of receptor\u2010interacting protein kinase 3 (RIPK3) in denervation atrophy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Sciatic denervation was induced in rats for initial time\u2010course transcriptomics and in mice for genetic and pharmacological studies. Assessments in wild\u2010type and RIPK3\u2010knockout mice included transcriptomics (RNA\u2010seq, qPCR), muscle morphology (wet weight ratio, cross\u2010sectional area), histological inflammation (H&amp;E, CD68 immunofluorescence), mitochondrial function (complex I\/V activity, ultrastructure and biogenesis\/fission regulators), STRING analysis to identify downstream effectors, validated key effectors NOX2 and NOX4 (qPCR\/Western blotting) and associated redox status (DHE staining), and analysis of myofibrillar protein content and proteolytic markers (Western blotting). Confirmatory studies included RIPK3 overexpression in C2C12 myotubes and its pharmacological inhibition (GSK872) in mice.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      RIPK3 emerged from transcriptomic analysis as an early upregulated mediator in denervated muscle, with protein levels increasing approximately threefold at 36\u2009h post\u2010injury. Genetic ablation of RIPK3 attenuated muscle atrophy, as shown by improved gastrocnemius wet weight ratio (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.0110). This protective effect was directly evidenced by a 40.7% increase in cross\u2010sectional area (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.04). The morphological preservation was accompanied by markedly suppressed expression of key atrophy markers, including MAFbx, MuRF1 and FoxO3a (all\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.01), and preserved MHC levels (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.0278). Mechanistically, RIPK3 knockout reduced inflammation, enhanced oxidative phosphorylation (GSEA FDR &lt;\u20090.001) and partially restored mitochondrial function, evidenced by significantly increased complex I (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.0438) and complex V (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.001) activity, preserved ultrastructure, upregulated PGC\u20101\u03b1 and NRF2 (both\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.05) and downregulated mitochondrial fission proteins (p\u2010DRP1, MFF, FIS1; all\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.01). STRING analysis predicted NOX4 as a key downstream effector, validated by reduced NOX4 protein (\u221246.6%,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.0366) and a consequent 52.2% decrease in ROS accumulation (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.001). Consistently, RIPK3 overexpression in C2C12 myotubes elevated NOX4 (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.0046) and atrophy markers, whereas pharmacological inhibition of RIPK3 in mice replicated the protective phenotype, increasing muscle wet weight ratio (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.0277) and suppressing NOX4 (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.0398) and proteolytic markers.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Denervation activates RIPK3 as a master regulator that drives muscle atrophy via NOX4\/ROS\u2010induced mitochondrial dysfunction, sustained inflammation and ubiquitin\u2013proteasome activation. Targeting RIPK3 preserves muscle mass and may offer a novel therapeutic strategy for neurogenic muscle atrophy, with possible implications for related wasting disorders.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/jcsm.70311","type":"journal-article","created":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T08:03:37Z","timestamp":1777622617000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["RIPK3 Inhibition Mitigates Denervated Muscle Atrophy via NOX4\u2010Mediated Mitochondrial Restoration and Inflammation Suppression"],"prefix":"10.1002","volume":"17","author":[{"given":"Yuntian","family":"Shen","sequence":"first","affiliation":[{"name":"Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education Medical School of Nantong University, Co\u2010Innovation Center of Neuroregeneration, Nantong University  Nantong Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen","family":"Zhang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education Medical School of Nantong University, Co\u2010Innovation Center of Neuroregeneration, Nantong University  Nantong Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zihao","family":"Zhao","sequence":"additional","affiliation":[{"name":"Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education Medical School of Nantong University, Co\u2010Innovation Center of Neuroregeneration, Nantong University  Nantong Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia","family":"Yi","sequence":"additional","affiliation":[{"name":"Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education Medical School of Nantong University, Co\u2010Innovation Center of Neuroregeneration, Nantong University  Nantong Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinlei","family":"Yao","sequence":"additional","affiliation":[{"name":"Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education Medical School of Nantong University, Co\u2010Innovation Center of Neuroregeneration, Nantong University  Nantong Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bingqian","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Orthopedics Changshu Hospital Affiliated to Soochow University, First People's Hospital of Changshu City  Changshu Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1889-1561","authenticated-orcid":false,"given":"Hualin","family":"Sun","sequence":"additional","affiliation":[{"name":"Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education Medical School of Nantong University, Co\u2010Innovation Center of 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China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,5,1]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2021.105807"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2025.116799"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2025.117326"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12967-023-04694-3"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1093\/rb\/rbaf050"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcsm.70010"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.adm8857"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12967-023-04369-z"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.3390\/antiox11091686"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcsm.70119"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mtbio.2025.102092"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bioactmat.2024.12.005"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.arr.2022.101810"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2019.01298"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2023.115664"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10787-024-01454-7"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcsm.13381"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2022.115186"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcsm.12395"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcsm.13704"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2020.101774"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13287-025-04175-y"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12035-024-04590-x"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1038\/s12276-022-00868-z"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41418-024-01281-x"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.123.068595"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.metabol.2024.155982"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-06057-9"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcsm.13265"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.3389\/fncel.2021.663384"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.21037\/atm-20-7269"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cellsig.2022.110355"},{"key":"e_1_2_8_34_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms232213880"},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-023-04827-3"},{"key":"e_1_2_8_36_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.730070"},{"key":"e_1_2_8_37_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcsm.12867"},{"key":"e_1_2_8_38_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.15472"},{"key":"e_1_2_8_39_1","doi-asserted-by":"publisher","DOI":"10.1186\/s11658-024-00572-y"},{"key":"e_1_2_8_40_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2022.102474"},{"key":"e_1_2_8_41_1","doi-asserted-by":"publisher","DOI":"10.1097\/JS9.0000000000000789"}],"container-title":["Journal 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