biostudies-literatureOuyang FNational Natural Science Foundation of ChinaShanghai Basic Research Field Project "Science and Technology Innovation Action Plan"National Key Research and Development Program of Chinae07048https://www.ebi.ac.uk/biostudies/studies/S-EPMC12806313biostudies-literatureUnknown13(3)The transient accumulation of triglyceride (TG)-enriched lipid droplets (LDs) in hepatocytes during early liver regeneration is critical for generation but remains mechanistically unclear, particularly the roles of LD fusion-associated proteins in lipid mobilization. Here, through integrated lipidomic and transcriptomic analyses, Cell death-inducing DNA fragmentation factor-like Effector C (CIDEC), an LD-associated 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)-driven regeneration. This pro-regenerative effect is abolished by FAAdvanced science (Weinheim, Baden-Wurttemberg, Germany)CIDEC Restricts Liver Regeneration by Disturbing Lipid Droplet Triglyceride Turnover.PMC1280631321JC14004003257148732300956322713342021YFA08048012024YFA1802800322715173227072492357302Yang HShen KZhao TJLi PLi RSu HChen FJShi YLuo DYang TSLi YHu CGui QZhang ZOuyang FGao LSun FfalseCIDEC Restricts Liver Regeneration by Disturbing Lipid Droplet Triglyceride Turnover.The transient accumulation of triglyceride (TG)-enriched lipid droplets (LDs) in hepatocytes during early liver regeneration is critical for generation but remains mechanistically unclear, particularly the roles of LD fusion-associated proteins in lipid mobilization. Here, through integrated lipidomic and transcriptomic analyses, Cell death-inducing DNA fragmentation factor-like Effector C (CIDEC), an LD-associated 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)-driven regeneration. This pro-regenerative effect is abolished by FA2026-01-01T00:00:00Z2026 Jan2026-06-06T15:07:47.236Z2026-06-01T03:10:43.682ZS-EPMC128063134125522010.1002/advs.202507048