{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T11:36:50Z","timestamp":1785411410916,"version":"3.56.0"},"reference-count":50,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T00:00:00Z","timestamp":1774569600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["82070691"],"award-info":[{"award-number":["82070691"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"award":["82070691"],"award-info":[{"award-number":["82070691"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The limited and inconsistent efficacy of existing therapies for tuberous sclerosis complex (TSC) has driven the exploration of novel strategies, including epigenetic regulation. GSK-J4, an inducer of global H3K27me3 accumulation, shows broad anti-tumor activity. However, its therapeutic potential in TSC remains unclear. In the study, we reported that GSK-J4 inhibited cell cycle progression and induced apoptosis in primary Tsc1+\/\u2212 and Tsc2+\/\u2212 MEFs. Mechanistically, Tsc1 or Tsc2 deletion reduced global H3K27me3, correlating with increased viability, accelerated cell cycle, and suppressed apoptosis-phenotypes reversed by GSK-J4. Moreover, GSK-J4 triggered endoplasmic reticulum stress (ERS) by activating the PERK-ATF4-CHOP axis, which concurrently downregulated the proto-oncogene c-Myc, outlining a GSK-J4\u2192p-PERK\u2192c-Myc inhibitory pathway. Notably, GSK-J4 synergized with rapamycin to enhance cell cycle arrest and apoptosis. In vivo, this combination alleviated renal impairment in Tsc1- or Tsc2-deficient models, suggesting a promising therapeutic strategy for TSC patients with suboptimal response to mammalian target of rapamycin complex 1 (mTORC1) inhibitors. Our study elucidates a specific ERS-dependent anti-tumor mechanism of GSK-J4 in Tsc-deficient contexts and demonstrates the synergistic efficacy of combining epigenetic and mTORC1 inhibitors.<\/jats:p>","DOI":"10.3390\/ijms27073067","type":"journal-article","created":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T15:45:42Z","timestamp":1774626342000},"page":"3067","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["GSK-J4 Suppresses Tumorigenesis by Targeting the PERK-c-Myc Pathway Through Endoplasmic Reticulum Stress Activation in Tuberous Sclerosis Complex"],"prefix":"10.3390","volume":"27","author":[{"given":"Xin","family":"Lei","sequence":"first","affiliation":[{"name":"Shanxi Provincial Key Laboratory of Medical Molecular Cell Biology, Institutes of Biomedical Sciences, Shanxi University, Taiyuan 030006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao","family":"Lang","sequence":"additional","affiliation":[{"name":"Shanxi Provincial Key Laboratory of Medical Molecular Cell Biology, Institutes of Biomedical Sciences, Shanxi University, Taiyuan 030006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6137-6154","authenticated-orcid":false,"given":"Ping","family":"Li","sequence":"additional","affiliation":[{"name":"Shanxi Provincial Key Laboratory of Medical Molecular Cell Biology, Institutes of Biomedical Sciences, Shanxi University, Taiyuan 030006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7416-1662","authenticated-orcid":false,"given":"Changxin","family":"Wu","sequence":"additional","affiliation":[{"name":"Shanxi Provincial Key Laboratory of Medical Molecular Cell Biology, Institutes of Biomedical Sciences, Shanxi University, Taiyuan 030006, China"},{"name":"Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education of China, Shanxi University, Taiyuan 030006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1007\/s12519-022-00576-8","article-title":"Modeling tuberous sclerosis complex with human induced pluripotent stem cells","volume":"20","author":"Niu","year":"2024","journal-title":"World J. 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