Phospholipid phosphatase 2 drives liver repair and regeneration after acute liver injury.

Acute liver injury is commonly caused by overdose-drug, toxins, or ischemia. The liver possesses a remarkable regenerative capacity, wherein metabolic remodeling plays a crucial role in restoring hepatic function and homeostasis. However, the specific metabolic shift that initiates hepatocyte regeneration remains unclear. Here, we employed multi-time-point multi-omics analyses to demonstrate that phosphatidylethanolamine undergoes a dynamic metabolic reprogramming, with phospholipid phosphatase 2 (PLPP2) exhibiting synchronous changes among the enzymes regulating PE metabolism. Liver biopsy samples from patients with drug-induced liver injury corroborated the PLPP2 alterations. In murine models, hepatocyte-specific deletion of PLPP2 exacerbated acute liver injury. Mechanistically, the resolution of ER stress was accompanied by a robust upregulation of PLPP2 during the regenerative phase. This shift promotes liver repair and regeneration by initiating the PE biosynthesis. PE, upon binding to PEBP1, modulated its affinity and strengthened its interaction with GLI1, thereby disrupting the association between lTCH and GLI1 and preventing the ubiquitination and degradation of GLI1. Additionally, PE promotes autophagy by facilitating the lipidation of LC3B. The increase in ER-localized PE mediated by PLPP2 also contributed to the alleviation of ER stress, thus establishing a positive feedback loop. Pharmacologic activation of PLPP2 or supplementation with ethanolamine may represent a promising therapeutic strategy for acute liver injury.