Multi-omics reveals the DR5-FXR-CHPT1 axis governs hepatocyte pyroptosis via glycerophospholipid remodeling after major partial hepatectomy

Background & Aims: Acute liver injury following major partial hepatectomy (PHx), manifesting as small-for-size syndrome (SFSS) and post-hepatectomy liver failure (PHLF), carries high mortality. However, the key mechanisms underlying irreversible remnant liver injury and cell death remain poorly understood, particularly regarding the contribution of lipid metabolism. This study investigates the contribution of lipid metabolism remodeling to post-hepatectomy hepatocyte injury and identifies potential therapeutic targets. Methods: We integrated murine graded PHx models, human liver tissues from associating liver partition and portal vein ligation for staged hepatectomy (ALPPS), multi-omics, and machine learning to identify key regulatory genes. Underlying mechanisms were validated via in vitro and in vivo genetic manipulation, alongside pharmacological modulation. Results: We revealed that aberrant glycerophospholipid metabolism is the primary driver of endoplasmic reticulum stress (ERS) -mediated pyroptosis in the remnant liver. Multi-omics analysis combined with machine learning identified death receptor 5 (DR5) as a critical regulator. Mechanistically, DR5 physically impeded the nuclear translocation of the Farnesoid X Receptor (FXR), thereby repressing the transcription of Chpt1 (Cholinephosphotransferase 1). The consequent deficiency in phosphatidylcholine (PC) compromised ER membrane integrity, exacerbating the Unfolded Protein Response and triggering lethal pyroptosis. Restoring the DR5-FXR-CHPT1 axis via AAV-mediated DR5 knockdown, FXR agonists, or exogenous PC supplementation significantly alleviated post-hepatectomy liver injury. Conclusions: Our study uncovers a non-canonical metabolic function of DR5 that disrupts ER membrane homeostasis via the FXR-CHPT1 axis, leading to fatal hepatocyte pyroptosis. Targeting this active metabolic reprogramming offers a promising therapeutic strategy to prevent PHLF and SFSS after major PHx.