03043nas a2200373   4500000000100000008004100001260001500042653001900057653001900076653001800095653002300113100001500136700001600151700001600167700001500183700001400198700001400212700001200226700001500238700001600253700001800269700001600287700001700303700001600320700001200336700001500348700001500363245015800378856007200536300001200608490000700620520202800627022001402655       2026                            d  c2026-04-0110a3D bioprinting10aHepatorganoids10aLiver failure10aLiver regeneration1 aZhichao Ye1 aJianing Yan1 aYuheng Wang1 aYiheng Lin1 aChao Wang1 aQuan Yang1 aTong Ji1 aEnjie Zhou1 aQiang Zheng1 aDanyang Zhong1 aYuyang Yuan1 aTingting Yan1 aZiyuan Wang1 aJun Yin1 aXiujun Cai1 aYifan Wang00aThree-dimensional bioprinted hiHeps hepatorganoids with enhanced hepatic functions for the treatment of liver failure and promotion of liver regeneration  uhttps://www.sciencedirect.com/science/article/pii/S2452199X25006140  a550-5730 v583 aThe intricate architecture of the liver, combined with its limited regenerative ability in severe injury, has spurred the development of innovative approaches for hepatic repair and functional restoration. Three-dimensional (3D) bioprinting provides a unique platform to reconstruct biomimetic liver tissues through spatially orchestrated cellular and extracellular matrix integration. Here, we developed 3D bioprinted hepatorganoids derived from human induced hepatocytes (hiHeps), which faithfully recapitulate the native lobular zonation crucial for spatially segregated metabolic functions in vivo. 3D bioprinted hiHeps hepatorganoids (3DP-HHO) exhibited markedly enhanced metabolic performance, including improved glucose and lipid regulation and elevated albumin synthesis, highlighting their potential as advanced liver models. The hepatorganoids demonstrated robust regenerative potential, which reversed chronic liver fibrosis (CLF) by resolving pathological collagen deposition, rescued acute liver failure (ALF) through rapid functional compensation, and accelerated liver regeneration in partial hepatectomy models by stimulating endogenous hepatocyte proliferation. Preclinical validation of post-hepatectomy liver failure (PHLF) model revealed that the implantation of 3DP-HHO significantly improved survival outcomes and promoted liver regeneration, compared to controls. In the future, by integrating patient-specific cells with regulable 3D microenvironments, our platform will achieve superior functional integration and regenerative efficacy over conventional approaches. This work establishes a paradigm for bioengineered liver grafts that actively drive tissue repair and regeneration. As a scalable and physiologically relevant approach, these bioprinted hepatic units pioneer a transformative strategy in regenerative hepatology, addressing critical challenges in treating liver failure and post-resection recovery while illuminating microenvironmental factors essential for organ-level regeneration.  a2452-199X