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Here, through integrated lipidomic and transcriptomic analyses, Cell death\u2010inducing DNA fragmentation factor\u2010like Effector C (CIDEC), an LD\u2010associated protein upregulated during this phase is identified, as a negative regulator of regeneration through its unexpected role in sequestering TG within LDs. Mechanistically, CIDEC acts as a metabolic gatekeeper: its depletion after peak LD accumulation promotes TG mobilization and enhances fatty acid oxidation (FAO)\u2010driven regeneration. This pro\u2010regenerative effect is abolished by FAO inhibition, underscoring the central role of TG catabolism. Conversely, overexpression of CIDEC or the TG biosynthetic enzyme Diacylglycerol O\u2010acyltransferase 2 (DGAT2) exacerbates TG retention and impairs liver regeneration. Notably, CIDEC depletion significantly improves regenerative outcomes in mice with chronic steatosis. These findings reveal a previously unrecognized role for LD fusion in regulating the TG storage\u2010utilization balance, where its suppression promotes metabolic flexibility to meet the energetic demands of liver regeneration. This metabolic checkpoint may be targeted to overcome impaired liver regeneration associated with fatty liver disease.<\/jats:p>","DOI":"10.1002\/advs.202507048","type":"journal-article","created":{"date-parts":[[2025,11,19]],"date-time":"2025-11-19T09:10:42Z","timestamp":1763543442000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["CIDEC Restricts Liver Regeneration by Disturbing Lipid Droplet Triglyceride Turnover"],"prefix":"10.1002","volume":"13","author":[{"given":"Feng","family":"Ouyang","sequence":"first","affiliation":[{"name":"Shanghai Key Laboratory of Metabolic Remodeling and Health Institute of Metabolism and Integrative Biology Fudan University Shanghai 200438 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yining","family":"Li","sequence":"additional","affiliation":[{"name":"Shanghai Key Laboratory of Metabolic Remodeling and Health Institute of Metabolism and Integrative 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