{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T17:56:23Z","timestamp":1790272583386,"version":"4.1.0"},"reference-count":57,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2024,12,26]],"date-time":"2024-12-26T00:00:00Z","timestamp":1735171200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["febs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The FEBS Journal"],"published-print":{"date-parts":[[2025,4]]},"abstract":"<jats:p>\n                    The prevalence of metabolic dysfunction\u2010associated steatotic liver disease (MASLD) progressing to metabolic dysfunction\u2010associated steatohepatitis (MASH), characterized by hepatic inflammation, has significantly increased in recent years due to unhealthy dietary practices and sedentary lifestyles. Cathepsin D (CTSD), a lysosomal protease involved in lipid homeostasis, is linked to abnormal lipid metabolism and inflammation in MASH. Although primarily intracellular, CTSD can be secreted extracellularly. Our previous proteomics research has shown that inhibition of extracellular CTSD results in more anti\u2010inflammatory effects and fewer potential side effects compared to intracellular CTSD inhibition. However, the correlation between reduced side effects and alterations in the hepatic lipid composition remains unknown. This study aims to investigate the correlation between intra\u2010 and extracellular CTSD inhibition and potential alterations in the hepatic lipid composition in MASH. Low\u2010density lipoprotein receptor knockout (\n                    <jats:italic>Ldlr<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>\u2212\/\u2212<\/jats:italic>\n                    <\/jats:sup>\n                    ) mice were fed a high\u2010fat diet for 10\u2009weeks and received subcutaneous injections every 2\u2009days of vehicle, intracellular CTSD inhibitor (GA\u201012), or extracellular CTSD inhibitor (CTD\u2010002). Matrix\u2010assisted laser desorption\/ionization mass spectrometry imaging (MALDI\u2010MSI) was used to visualize and compare the lipid composition in liver tissues. Hepatic phosphatidylcholine remodeling was observed with both inhibitors, suggesting their therapeutic potential in treating MASH. Treatment with an intracellular CTSD inhibitor resulted in elevated levels of cardiolipin, reactive oxygen species, phosphatidylinositol, phosphatidylethanolamine, and lipids that are linked to mitochondrial dysfunction and inflammation, and induced more oxidative stress. The observed modifications in lipid composition demonstrate the clinical advantages of extracellular CTSD inhibition as a potentially beneficial therapeutic approach for MASH.\n                  <\/jats:p>","DOI":"10.1111\/febs.17358","type":"journal-article","created":{"date-parts":[[2024,12,27]],"date-time":"2024-12-27T00:40:36Z","timestamp":1735260036000},"page":"1781-1797","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Inhibition of intracellular versus extracellular cathepsin D differentially alters the liver lipidome of mice with metabolic dysfunction\u2010associated steatohepatitis"],"prefix":"10.1111","volume":"292","author":[{"given":"Isabeau","family":"Vermeulen","sequence":"first","affiliation":[{"name":"Maastricht Multimodal Molecular Imaging Institute (M4i) University of Maastricht  The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengying","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Genetics and Cell Biology, Institute of Nutrition and Translational Research in Metabolism (NUTRIM) Maastricht University  The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hester","family":"van Mourik","sequence":"additional","affiliation":[{"name":"Department of Genetics and Cell Biology, Institute of Nutrition and Translational Research in Metabolism (NUTRIM) Maastricht University  The Netherlands"},{"name":"Department of Precision Medicine, Institute for Oncology and Reproduction (GROW) Maastricht University  The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tulasi","family":"Yadati","sequence":"additional","affiliation":[{"name":"Department of Genetics and Cell Biology, Institute of Nutrition and Translational Research in Metabolism (NUTRIM) Maastricht University  The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gert","family":"Eijkel","sequence":"additional","affiliation":[{"name":"Maastricht Multimodal Molecular Imaging Institute (M4i) University of Maastricht  The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin","family":"Balluff","sequence":"additional","affiliation":[{"name":"Maastricht Multimodal Molecular Imaging Institute (M4i) University of Maastricht  The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roger","family":"Godschalk","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Institute for Nutrition and Translational Research in Metabolism (NUTRIM) Maastricht University  The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lieve","family":"Temmerman","sequence":"additional","affiliation":[{"name":"Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM) Maastricht University Medical Center (UMC)  The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erik A. 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