Therapeutic priming of liver regeneration: from mechanisms to ex vivo machine perfusion.

The liver's extraordinary regenerative capacity has fascinated biologists for decades, yet the translation of regenerative biology into clinically effective therapies remains limited. Regeneration is not a simple proliferative response but a tightly orchestrated program initiated by tissue injury and coordinated through inflammatory priming, complement activation, mechanosensory signaling, extracellular matrix remodeling, metabolic reprogramming, and growth factor-driven hepatocyte proliferation. In this review, we synthesize current understanding of the cellular and molecular networks that govern liver regeneration, emphasizing the dynamic crosstalk among hepatocytes, Kupffer cells, liver sinusoidal endothelial cells, hepatic stellate cells, and recruited immune populations. We further examine the major experimental systems used to study regeneration, from classic in vivo hepatectomy models to emerging human-relevant platforms, including organoids, liver-on-a-chip systems, extracellular matrix scaffolds, precision-cut liver slices, and ex vivo perfusion, highlighting both their mechanistic value and translational limitations. We then focus on the growing clinical importance of regeneration in transplantation, where the expanding use of marginal, steatotic, aged, and reduced-size grafts has intensified the need to preserve regenerative competence. In this context, ex vivo machine perfusion offers a uniquely promising platform to study, modulate, and therapeutically prime regenerative pathways before implantation, potentially enabling graft reconditioning strategies that improve outcomes in small-for-size and other high-risk liver grafts.