{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T10:03:17Z","timestamp":1784887397745,"version":"3.55.0"},"reference-count":40,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2026,4,24]],"date-time":"2026-04-24T00:00:00Z","timestamp":1776988800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,4,24]],"date-time":"2026-04-24T00:00:00Z","timestamp":1776988800000},"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":["82272925"],"award-info":[{"award-number":["82272925"]}],"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":["82274151"],"award-info":[{"award-number":["82274151"]}],"id":[{"id":"10.13039\/501100001809","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":"ABSTRACT<\/jats:title>\n \n Background<\/jats:title>\n \n Cancer cachexia is a debilitating syndrome characterized by severe skeletal muscle wasting, which significantly impairs patient quality of life and survival. Indoleamine 2,3\u2010dioxygenase 1 (IDO1), a key enzyme in tryptophan (Trp) metabolism, is often upregulated in cancers, but its specific role in driving lung cancer\u2013associated cachexia remains inadequately defined. This study investigated the mechanistic role of\n Ido1<\/jats:italic>\n in cancer cachexia and evaluated the therapeutic potential of its inhibition.\n <\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n We established Lewis lung carcinoma (LLC) models in C57BL\/6 mice using wild\u2010type,\n Ido1<\/jats:italic>\n \u2010overexpressing (\n Ido1<\/jats:italic>\n \u2010OE) and\n Ido1<\/jats:italic>\n \u2010knockout (\n Ido1<\/jats:italic>\n \u2010KO) cells. Muscle mass, tumour growth and metabolic changes were assessed in\u00a0vivo. Transcriptomic and targeted metabolomic analyses were performed on muscle and serum samples. In\u00a0vitro, we examined the effects of tumour\u2010conditioned media, the Trp metabolite kynurenine (Kyn) and Trp supplementation on C2C12 myotube atrophy. In\u00a0vivo experiments verified the efficacy of the\n Ido1<\/jats:italic>\n inhibitor palmatine hydrochloride (PAL). Molecular pathways were analysed via western blot and qPCR.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Compared to LLC mouse models,\n Ido1<\/jats:italic>\n \u2010OE significantly exacerbated tumour growth and cachexia, leading to a significant decrease in lean body weight, gastrocnemius and tibialis anterior muscle weights (\n p<\/jats:italic>\n \u2009<\u20090.01,\n p\u2009<<\/jats:italic>\n \u20090.0001,\n p<\/jats:italic>\n \u2009<\u20090.001). Gastrocnemius muscle fibre cross\u2010sectional area significantly decreased in the\n Ido1<\/jats:italic>\n \u2010OE group (\n p<\/jats:italic>\n \u2009<\u20090.0001). Transcriptomic analysis revealed that\n Ido1\u2010<\/jats:italic>\n OE activated pro\u2010inflammatory and protein degradation pathways (upregulating MuRF1\/Atrogin1,\n p<\/jats:italic>\n \u2009<\u20090.05) while suppressing anabolic signalling pathways (oestrogen pathways,\n p<\/jats:italic>\n \u2009<\u20090.01). Metabolomics analysis revealed unique metabolic signatures in\n Ido1<\/jats:italic>\n \u2010OE mice: Trp depletion and Kyn accumulation. In\u00a0vitro experiments demonstrated that\n Ido1\u2010<\/jats:italic>\n OE enhanced LLC cell proliferation and migration capabilities (\n p<\/jats:italic>\n \u2009<\u20090.0001,\n p<\/jats:italic>\n \u2009<\u20090.0001). Tumour\u2010conditioned medium (TCM) derived from\n Ido1<\/jats:italic>\n \u2010OE tumours significantly induced C2C12 myotube atrophy (\n p<\/jats:italic>\n \u2009<\u20090.01). Similarly, direct treatment with Kyn led to dose\u2010dependent muscle fibre shrinkage, with significant atrophy observed at 30\u2009\u03bcM (\n p<\/jats:italic>\n \u2009<\u20090.01) and 100\u2009\u03bcM (\n p<\/jats:italic>\n \u2009<\u20090.0001). Notably, the myotube atrophy induced by Kyn was significantly reversed by the addition of supplemental Trp (\n p<\/jats:italic>\n \u2009<\u20090.0001). Compared with the\n Ido1<\/jats:italic>\n \u2010OE group, PAL treatment reduced gastrocnemius and tibialis anterior atrophy (\n p<\/jats:italic>\n \u2009<\u20090.01;\n p<\/jats:italic>\n \u2009<\u20090.05). Mechanistically, PAL inhibited the mRNA expression levels of MuRF1\/Atrogin1 (\n p<\/jats:italic>\n \u2009<\u20090.0001,\n p<\/jats:italic>\n \u2009<\u20090.001), as well as their corresponding protein levels (\n p<\/jats:italic>\n \u2009<\u20090.0001,\n p<\/jats:italic>\n \u2009<\u20090.0001). Furthermore, PAL restored the phosphorylation level of mTOR (\n p<\/jats:italic>\n \u2009<\u20090.001), as well as the mRNA expression of myosin heavy chain (\n p<\/jats:italic>\n \u2009<\u20090.01).\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n \n Our findings demonstrate that\n Ido1<\/jats:italic>\n accelerates muscle atrophy and cancer cachexia by driving a metabolic reprogramming centred on the Trp\u2013Kyn pathway. Pharmacological inhibition of\n Ido1<\/jats:italic>\n with PAL effectively mitigates these effects, positioning\n Ido1<\/jats:italic>\n as a promising therapeutic target for treating cancer cachexia.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1002\/jcsm.70295","type":"journal-article","created":{"date-parts":[[2026,4,24]],"date-time":"2026-04-24T12:00:22Z","timestamp":1777032022000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Cancer IDO1\u2010Mediated Tryptophan\u2013Kynurenine Metabolic Reprogramming to Drive Skeletal Muscle Atrophy and Cachexia Acceleration"],"prefix":"10.1002","volume":"17","author":[{"given":"Leng","family":"Han","sequence":"first","affiliation":[{"name":"Department of Pharmacy Shanghai Sixth People's Hospital Affiliated Shanghai Jiao Tong University School of Medicine Shanghai 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China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu","family":"Bai","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Shanghai Sixth People's Hospital Affiliated Shanghai Jiao Tong University School of Medicine Shanghai China"},{"name":"School of Biological and Biomedical Engineering Donghua University Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Fang","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Shanghai Sixth People's Hospital Affiliated Shanghai Jiao Tong University School of Medicine Shanghai China"},{"name":"School of Biological and Biomedical Engineering Donghua University Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuxuan","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Shanghai Sixth People's Hospital Affiliated Shanghai Jiao Tong University School of Medicine Shanghai China"},{"name":"College of Food Science Shanghai Ocean University Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dingyuan","family":"Bai","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Shanghai Sixth People's Hospital Affiliated Shanghai Jiao Tong University School of Medicine Shanghai China"},{"name":"College of Food Science Shanghai Ocean University Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Shanghai Sixth People's Hospital Affiliated Shanghai Jiao Tong University School of Medicine Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yonglong","family":"Han","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Shanghai Sixth People's Hospital Affiliated Shanghai Jiao Tong University School of Medicine Shanghai China"},{"name":"College of Food Science Shanghai Ocean University Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheng","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Shanghai Sixth People's Hospital Affiliated Shanghai Jiao Tong University School of Medicine Shanghai China"},{"name":"Shanghai University of Traditional Chinese Medicine Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shumin","family":"Zhou","sequence":"additional","affiliation":[{"name":"Institute of Microsurgery on Extremities Shanghai Sixth People's Hospital Affiliated Shanghai Jiao Tong University School of Medicine Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Quanjun","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Shanghai Sixth People's Hospital Affiliated Shanghai Jiao Tong University School of Medicine Shanghai China"},{"name":"School of Biological and Biomedical Engineering Donghua University Shanghai China"},{"name":"College of Food Science Shanghai Ocean University Shanghai 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of Cachexia, Sarcopenia and Muscle"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jcsm.70295","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/jcsm.70295","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jcsm.70295","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T09:18:39Z","timestamp":1784884719000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/jcsm.70295"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,24]]},"references-count":40,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2026,6]]}},"alternative-id":["10.1002\/jcsm.70295"],"URL":"https:\/\/doi.org\/10.1002\/jcsm.70295","archive":["Portico"],"relation":{},"ISSN":["2190-5991","2190-6009"],"issn-type":[{"value":"2190-5991","type":"print"},{"value":"2190-6009","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,24]]},"assertion":[{"value":"2025-12-07","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication 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