{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T10:15:41Z","timestamp":1788344141093,"version":"build-2803163510"},"reference-count":40,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T00:00:00Z","timestamp":1773878400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T00:00:00Z","timestamp":1773878400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100008731","name":"Nakatomi Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008731","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":[[2026,4]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Cancer cachexia is a complex syndrome marked by weight loss and muscle wasting, significantly impacting patient quality of life and survival. Mechanistically, it is characterized by suppressed protein synthesis and enhanced muscle catabolism, with the role of endoplasmic reticulum (ER) stress and unfolded protein response (UPR) becoming increasingly evident. This study aimed to explore ER stress\u2013tolerant factors in muscle wasting and evaluate their potential to prevent muscle loss in cancer cachexia.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>A genome\u2010wide CRISPR screening was conducted in the context of ER stress\u2013mediated growth inhibition of C2C12 myoblasts. The candidate genes resistant to ER stress were further evaluated in C2C12 myotubes treated with conditioned medium of Lewis lung adenocarcinoma (LLC) cells. Twelve\u2010week\u2010old male mice were administered LLC cells and shRNA against Naa35 via adeno\u2010associated virus. Four weeks later, tibialis anterior (TA) muscles were analysed for muscle mass, grip strength and molecular changes with quantitative polymerase chain reaction, western blotting and histological analysis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      CRISPR screening identified Naa35, Naa38 and Naa30, all three components of N\u2010terminal acetyltransferase C, as key molecules for resistance to ER stress. The atrophic muscles of mice bearing LLC demonstrated an elevation of UPR, as well as 1.64\u2010fold upregulation of Naa35 protein (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.0072). Among the three branches of the UPR, an ATF6 inhibitor, AEBSF, abolished upregulation of Naa35, Naa38 and Naa30, and an ATF6 activator, AA147, induced Naa35 expression in a dose\u2010dependent manner (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.001). In cells treated with LLC conditioned medium, Naa35 knockdown reduced the amount of cathepsin K (CTSK) protein, which subsequently resulted in the CTSK\u2010mediated proteolysis of insulin receptor substrate 1. In LLC\u2010bearing mice, Naa35 knockdown led to a 65.4% reduction in CTSK protein expression (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.001) and preservation of the phosphorylation levels of protein kinase B (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.0324) and anabolic\u2010related S6 kinase (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.0375). Concurrently, the expression of catabolism\u2010related genes was repressed (MuRF1,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.0015; MAFbx1,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.0265). These alterations were associated with the restoration of TA muscle mass (2.52\u2009\u00b1\u20090.19 vs. 3.72\u2009\u00b1\u20090.45\u2009mg\/g,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.0004), fibre area (1741\u2009\u00b1\u2009992 vs. 2099\u2009\u00b1\u20091264\u2009mm\n                      <jats:sup>2<\/jats:sup>\n                      ,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.0001), grip strength in all four limbs (0.0328\u2009\u00b1\u20090.0076 vs. 0.0506\u2009\u00b1\u20090.0130\u2009N\/g,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.0295) and wire mesh hanging time (496\u2009\u00b1\u2009331 vs. 1038\u2009\u00b1\u2009370\u2009s,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.0406).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Inhibition of N\u2010terminal acetyltransferase C prevents ER stress\u2013induced muscle wasting via the downregulation of CTSK and subsequent activation of the anabolic pathway. This suggests that N\u2010terminal acetyltransferase C is a potential therapeutic target for combating muscle wasting in cancer cachexia.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/jcsm.70249","type":"journal-article","created":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T07:20:51Z","timestamp":1773904851000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Inhibition of N\u2010Terminal Acetyltransferase C Mitigates Endoplasmic Reticulum Stress\u2013Mediated Muscle Atrophy in Cancer Cachexia"],"prefix":"10.1002","volume":"17","author":[{"given":"Yusaku","family":"Kaneko","sequence":"first","affiliation":[{"name":"Department of Cardiovascular Medicine, Graduate School of Medical Science Kyoto Prefectural University of Medicine  Kyoto Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomohiro","family":"Hino","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, Graduate School of Medical Science Kyoto Prefectural University of Medicine  Kyoto Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shunta","family":"Taminishi","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, Graduate School of Medical Science Kyoto Prefectural University of Medicine  Kyoto Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yayoi","family":"Matoba","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Graduate School of Medical Science Kyoto Prefectural University of Medicine  Kyoto Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daisuke","family":"Motooka","sequence":"additional","affiliation":[{"name":"Department of Infection Metagenomics, Research Institute for Microbial Diseases Osaka University  Osaka Japan"},{"name":"Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives (OTRI) Osaka University  Osaka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4015-1319","authenticated-orcid":false,"given":"Atsushi","family":"Hoshino","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, Graduate School of Medical Science Kyoto Prefectural University of Medicine  Kyoto Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satoaki","family":"Matoba","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, Graduate School of Medical Science Kyoto Prefectural University of Medicine  Kyoto 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