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However, mTORC1-independent mechanisms in this disorder remain poorly understood. In the study, excess glycogen storage was found in\n                    <jats:italic>Tsc1<\/jats:italic>\n                    <jats:sup>\u2013\/\u2013<\/jats:sup>\n                    cells,\n                    <jats:italic>Tsc1<\/jats:italic>\n                    <jats:sup>+\/\u2013<\/jats:sup>\n                    and\n                    <jats:italic>Tsc1<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>c.2500-2503delAACA<\/jats:italic>\n                    <\/jats:sup>\n                    mice, as well as in\n                    <jats:italic>Tsc2<\/jats:italic>\n                    <jats:sup>\u2013\/\u2013<\/jats:sup>\n                    cells,\n                    <jats:italic>Tsc2<\/jats:italic>\n                    <jats:sup>+\/<\/jats:sup>\n                    <jats:sup>\u2013<\/jats:sup>\n                    and\n                    <jats:italic>Tsc2<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>c.1113delA<\/jats:italic>\n                    <\/jats:sup>\n                    mice, with more pronounced accumulation in models with\n                    <jats:italic>TSC2<\/jats:italic>\n                    defects. Mechanistically, the deficiency of\n                    <jats:italic>TSC1<\/jats:italic>\n                    or\n                    <jats:italic>TSC2<\/jats:italic>\n                    gene caused redundant uncomplexed-TSC2 or TSC1 protein, respectively. Strikingly, only uncomplexed-TSC1 downregulated the histone demethylase KDM5A, which in turn increased H3K4me3 levels at the\n                    <jats:italic>METTL3<\/jats:italic>\n                    promoter to enhance its expression. The upregulated m\n                    <jats:sup>6<\/jats:sup>\n                    A \u201cwriter\u201d protein METTL3 cooperated with the \u201creader\u201d protein IGF2BP2 to stabilize\n                    <jats:italic>GYS2<\/jats:italic>\n                    mRNA, causing the upregulation of GYS2 resulting in the glycogen storage. Thus, our study uncovered a novel mTORC1 independent pathway (TSC1-KDM5A-METTL3-IGF2BP2-GYS2) that underlies the excess glycogen storage, and that synergy of mTORC1-dependent and independent pathways leads to the more pronounced glycogen storage with\n                    <jats:italic>TSC2<\/jats:italic>\n                    defects compared to those with\n                    <jats:italic>TSC1<\/jats:italic>\n                    defects, reflecting the more severer clinical phenotypes in TSC patients with\n                    <jats:italic>TSC2<\/jats:italic>\n                    mutations. Importantly, the restoration of glycogen homeostasis and significant amelioration of liver lesion in\n                    <jats:italic>TSC2<\/jats:italic>\n                    defect models after the combination treatment of pharmacological inhibitors targeting mTORC1 and METTL3, unveil a potential clinic intervention for TSC patients to whom mTORC1 inhibitors are less effective or even ineffective.\n                  <\/jats:p>","DOI":"10.1038\/s41419-025-08161-3","type":"journal-article","created":{"date-parts":[[2025,11,14]],"date-time":"2025-11-14T16:33:21Z","timestamp":1763138001000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Uncomplexed-TSC1 deploys novel mTORC1-independent pathway to exacerbate the liver glycogen storage in TSC"],"prefix":"10.1038","volume":"16","author":[{"given":"Xiaoqiao","family":"Yue","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanping","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0472-5909","authenticated-orcid":false,"given":"Na","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao","family":"Lang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guangxin","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiuhong","family":"Xiong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenjing","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6137-6154","authenticated-orcid":false,"given":"Ping","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7416-1662","authenticated-orcid":false,"given":"Changxin","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,11,14]]},"reference":[{"key":"8161_CR1","doi-asserted-by":"publisher","DOI":"10.1038\/nrdp.2016.35","volume":"2","author":"EP Henske","year":"2016","unstructured":"Henske EP, Jozwiak S, Kingswood JC, Sampson JR, Thiele EA. 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