{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T03:13:09Z","timestamp":1788232389527,"version":"build-2803163510"},"reference-count":55,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T00:00:00Z","timestamp":1788134400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T00:00:00Z","timestamp":1788134400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Pediatric Investigation"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Importance<\/jats:title>\n                    <jats:p>Metabolic dysfunction\u2010associated steatotic liver disease (MASLD) is caused by dysregulated lipid metabolism, inflammation, and mitochondrial dysfunction. Given the rising burden of MASLD in children and adolescents, identifying experimentally tractable mechanisms relevant to pediatric diseases is of considerable interest. Tryptophan hydroxylase\u20101 (TPH1), the rate\u2010limiting enzyme for peripheral serotonin synthesis, has been implicated in metabolic disorders, but its hepatic role in MASLD remains unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>\n                      To investigate whether\n                      <jats:italic>Tph1<\/jats:italic>\n                      suppression alleviates lipid accumulation, mitochondrial dysfunction, and hepatocyte injury through changes associated with Parkin\u2010mediated mitophagy.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      MASLD was induced in young adult male C57BL\/6J mice by a 12\u2010week high\u2010fat diet (HFD). At HFD onset, mice received a single tail\u2010vein injection of liver\u2010tropic AAV8\u2010shTph1 or the control AAV8. The HFD feeding was continued for 12 weeks until the end of the experiment. Hepatic histology, serum biochemistry, oxidative stress, inflammatory responses, apoptosis, and mitochondrial function were also evaluated. Mechanistic studies were conducted in palmitic acid\/oleic acid\u2010treated AML12 hepatocytes using siRNA targeting\n                      <jats:italic>Tph1<\/jats:italic>\n                      and\n                      <jats:italic>Parkin<\/jats:italic>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Hepatic TPH1 expression was elevated in MASLD mice.\n                      <jats:italic>Tph1<\/jats:italic>\n                      knockdown alleviated diet\u2010induced steatosis, reduced serum triglycerides, total cholesterol, low\u2010density lipoprotein cholesterol, and transaminase levels, suppressed oxidative stress, and attenuated inflammatory and fibrotic markers.\n                      <jats:italic>Tph1<\/jats:italic>\n                      silencing decreased hepatocyte apoptosis and restored mitochondrial function. Transmission electron microscopy and fractionated Western blotting analyses revealed increased Parkin\u2010associated mitophagy. In AML12 cells, siTph1 reduced lipid accumulation and apoptosis, whereas co\u2010silencing\n                      <jats:italic>Parkin<\/jats:italic>\n                      partially reversed these effects.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Interpretation<\/jats:title>\n                    <jats:p>\n                      Hepatic TPH1 is associated with MASLD progression and impaired Parkin\u2010mediated mitophagy.\n                      <jats:italic>Tph1<\/jats:italic>\n                      suppression may represent a potential therapeutic strategy for experimental MASLD, with possible translational relevance to pediatric MASLD, though direct clinical validation is still needed.\n                    <\/jats:p>\n                  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