Developing chemical reprogramming strategies of non-hepatocytes for liver regeneration

• Small molecules precisely modulate signaling pathways and epigenetic modifications to drive liver cell fate and regeneration. • Chemical reprogramming efficiently converts fibroblasts into functional hepatocyte-like cells through targeted mechanisms. • Advanced methods in chemical reprogramming enhance hepatocyte differentiation and maturation for potential applications. • The review explores in vivo chemical reprogramming on liver repair, highlighting combination therapies for improved outcomes. • Future directions in chemical reprogramming focus on specificity, efficiency, translational potential in biomedicine. Liver injury and the ensuing regenerative processes exert a profound impact on treatment outcomes. Conventional pharmacotherapy, nutritional adjuncts, and invasive interventions, despite their frequent utilization, often prove inefficacious. Chemical reprogramming, which employs small molecules to emulate extrinsic signaling cues, emerges as a promising therapeutic strategy for liver regeneration, analogous to the developmental processes governing cellular fate. However, its application in hepatic repair necessitates systematic integration. This review synthesizes the role of chemical reprogramming in liver regeneration research. It first delineates the mechanisms underlying chemical reprogramming, emphasizing the pivotal role of small molecules in facilitating hepatic regeneration through the modulation of specific signaling pathways and epigenetic modifications. Additionally, it details the derivation of hepatocyte-like cells via chemical reprogramming within the realm of tissue engineering. The review further explores the role of chemical reprogramming in promoting in vivo liver repair and regeneration, particularly within the context of combinatorial therapeutic strategies. Chemical reprogramming induces the reprogramming of non-hepatic cells into hepatocyte-like cells through the precise regulation of cellular signaling pathways and epigenetic modifications by small molecules, thereby achieving cellular composition remodeling in injured livers. Current liver regeneration strategies rely on the modulation of endogenous regenerative capacity and cell-based therapies; thus, elucidating the regenerative and reparative roles of chemical reprogramming in liver injury is imperative. Addressing the inherent challenges of chemical reprogramming in hepatic regeneration is also underscored.