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Lymphangioleiomyomatosis (LAM) is a progressive pulmonary disease affecting almost exclusively women. TSC and LAM are both caused by mutations in\n                    <jats:italic>TSC1<\/jats:italic>\n                    and\n                    <jats:italic>TSC2<\/jats:italic>\n                    that result in mTORC1 hyperactivation. Here, we report that single-cell RNA sequencing of LAM lungs identified activation of genes in the sphingolipid biosynthesis pathway. Accordingly, the expression of acid ceramidase (\n                    <jats:italic>ASAH1<\/jats:italic>\n                    ) and dihydroceramide desaturase (\n                    <jats:italic>DEGS1<\/jats:italic>\n                    ), key enzymes controlling sphingolipid and ceramide metabolism, was significantly increased in TSC2-null cells. TSC2 negatively regulated the biosynthesis of tumorigenic sphingolipids, and suppression of ASAH1 by shRNA or the inhibitor ARN14976 (17a) resulted in markedly decreased TSC2-null cell viability. In vivo, 17a significantly decreased the growth of TSC2-null cell\u2013derived mouse xenografts and short-term lung colonization by TSC2-null cells. Combined rapamycin and 17a treatment synergistically inhibited renal cystadenoma growth in\n                    <jats:italic>Tsc2<\/jats:italic>\n                    <jats:sup>+\/\u2013<\/jats:sup>\n                    mice, consistent with increased ASAH1 expression and activity being rapamycin insensitive. Collectively, the present study identifies rapamycin-insensitive ASAH1 upregulation in TSC2-null cells and tumors and provides evidence that targeting aberrant sphingolipid biosynthesis pathways has potential therapeutic value in mechanistic target of rapamycin complex 1\u2013hyperactive neoplasms, including TSC and LAM.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.166850","type":"journal-article","created":{"date-parts":[[2023,3,16]],"date-time":"2023-03-16T12:00:53Z","timestamp":1678968053000},"source":"Crossref","is-referenced-by-count":8,"title":["Upregulation of acid ceramidase contributes to tumor progression in tuberous sclerosis complex"],"prefix":"10.1172","volume":"8","author":[{"given":"Aristotelis","family":"Astrinidis","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio, 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