Reconstructing Liver Fibrosis: 3D Human Models, Microbiome Interfaces, and Therapeutic Innovation.

Liver fibrosis is a significant consequence of severe liver injury resulting from viral hepatitis, alcohol, and metabolic dysfunction. Progressive fibrosis and ultimate cirrhosis are leading causes of morbidity and mortality worldwide, generally irreversible and poorly targeted by current therapies. Traditional in vitro models and animal models mostly fail to fully recapitulate human multicellular crosstalk, extracellular matrix (ECM) remodeling, and the chronic, immune modulated nature of the disease. Recent advances in three-dimensional (3D) cell culture models including organoids, spheroids, bioprinted constructs, and organ-on-a-chip systems are advantageous for reconstructing cellular diversity and mechanical microenvironments to understand pathophysiology and aid in drug discovery. Emerging multi-organ models are capable of incorporating microbiome derived cues and using multi-omics readouts and imaging-enabled mechanistic dissection for more predictive anti-fibrotic screening. These technologies align well with the recent Modernization 3.0 regulation and New Approach Methodologies by the Food and Drug Administration (FDA) and recent EU Pharmaceutical Reform. This review summarizes the pathophysiology of liver fibrosis, the current landscape of 3D human liver models, and examines how microbiome interfaces modulate fibrogenesis.