Organoid-guided precision hepatology for metabolic liver disease

Metabolic dysfunction associated steatotic liver disease affects millions of people worldwide. Progress towards a definitive cure has been incremental and limited to only lifestyle modification. Hepatocyte-specific lipid accumulation is the main trigger of lipotoxic events, driving inflammafibrotic processes. The underlying pathology is extraordinarily heterogenous, and steatohepatitis manifestations are markedly influenced by metabolic communications across non-hepatic organs. Synthetic human tissue models have emerged as powerful platforms to better capture the mechanistic diversity in disease progression, while preserving individual-specific genetic traits. In this review, we will outline current research efforts focused on integrating multiple synthetic tissue models of key metabolic organs, with emphasis on organoid-based systems. By combining functional genomics and population-scale en masse profiling methodologies, human tissues derived from patients can provide insights into personalized genetic, transcriptional, biochemical, and metabolic states. These collective efforts will advance a more precise understanding of steatohepatitis toward developing preemptive, rational solutions for mechanism-directed diagnostic and therapeutic investigation.