CIDEC Restricts Liver Regeneration by Disturbing Lipid Droplet Triglyceride Turnover

Abstract 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 FAO inhibition, underscoring the central role of TG catabolism. Conversely, overexpression of CIDEC or the TG biosynthetic enzyme Diacylglycerol O‐acyltransferase 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‐utilization 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.