Molecular mechanisms mediated by liquid-liquid phase separation in chronic liver disease progression.

Liquid-liquid phase separation (LLPS) is a cellular process driven by multivalent interactions, forming dynamic biomolecular condensates containing proteins, RNAs, and other molecules. LLPS plays a pivotal role in processes such as signal transduction, gene expression, autophagy, and cellular stress responses. The dysregulation of LLPS is linked to chronic liver diseases (CLDs), particularly non-alcoholic fatty liver disease (NAFLD), liver fibrosis, and hepatocellular carcinoma (HCC). LLPS profoundly mediates the pathological evolution of these diseases by regulating key mechanisms, including lipid metabolism, inflammatory responses, and cell death. This review highlights the central role of LLPS in NAFLD progression, liver fibrosis, and HCC transformation. Furthermore, it evaluates the feasibility of targeting LLPS as a therapeutic strategy, proposing innovative approaches such as small-molecule inhibitors, protein modification regulators, and RNA interference to restore LLPS homeostasis. These strategies hold the potential to mitigate disease progression and prevent the transition to fibrosis and liver cancer.