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

Abstract Severe liver injury following major partial hepatectomy (PHx) carries high mortality, yet the mechanisms driving irreversible cell death remain poorly understood. Here we show that aberrant lipid metabolism drives inflammatory cell death in the remaining liver tissue. Integrating data from male mouse models and human tissues, we found that death receptor 5 (DR5) acts as a critical regulator. Mechanistically, DR5 impedes the nuclear entry of the Farnesoid X Receptor (FXR), repressing the production of phosphatidylcholine (PC), an essential structural lipid. This lipid deficiency compromises the integrity of cellular membranes, causing severe stress and lethal pyroptosis. Restoring this pathway via DR5 suppression, FXR activation, or PC supplementation significantly alleviated post-surgical liver injury. Overall, we uncover a non-canonical metabolic function of DR5 that disrupts cellular homeostasis. These findings suggest that modulating this metabolic pathway may offer potential avenues for investigating future management strategies for small-for-size syndrome (SFSS) and post-hepatectomy liver failure (PHLF).