ABSTRACT Liver failure remains a life‐threatening syndrome where the available therapeutic options are extremely limited beyond transplantation. This study addresses critical cell source and mechanistic challenges by developing a novel bioartificial liver (BAL) system. We utilized CRISPR/Cas9 technology to knockout the GGTA1 gene in primary porcine hepatocytes to reduce immunogenicity. These hepatocytes were co‐cultured with R‐spondin1‐overexpressing human umbilical vein endothelial cells (R‐HUVECs) to form functionally stable liver organoids. In ex vivo study using plasma from patients with acute‐on‐chronic liver failure (ACLF), the BAL system demonstrated superior detoxification, significantly reducing ammonia and bilirubin levels compared to traditional non‐bioartificial liver (NAL) support. Multi‐omics analyses revealed that BAL treatment actively restored metabolic homeostasis by promoting branched‐chain amino acid (BCAA) metabolism and upregulating lysophosphatidylcholine (LPC) species associated with membrane repair and anti‐inflammatory signaling. Significantly, this research demonstrates that unlike the passive physical filtration of NAL, BAL serves as an active biological regulator of systemic metabolism. These findings provide a robust theoretical and practical foundation for the clinical translation of BAL technology, offering a promising strategy to improve outcomes for liver failure patients by modulating systemic metabolism.
He et al. (Sun,) studied this question.