Fibroblast activation protein-α in liver fibrosis and hepatocarcinogenesis: Stromal remodeling, molecular imaging, and theranostic targeting.

Abstract

Liver fibrosis links chronic liver injury to cirrhosis, hepatic decompensation, and hepatocellular carcinoma (HCC), while current non-invasive tests mainly estimate fibrotic burden and incompletely capture active stromal biology. Fibroblast activation protein-α (FAPα), a cell-surface serine protease enriched in activated hepatic stellate cells (HSCs), myofibroblasts, and cancer-associated fibroblasts (CAFs), is a biologically informative and pharmacologically tractable stromal target because of its extracellular accessibility and compatibility with ligand-based imaging, protease-activated drug delivery, radionuclide therapy, and cellular therapeutic platforms. This review evaluates FAPα as a candidate druggable stromal hub across the fibrosis-HCC continuum while distinguishing FAPα expression, enzymatic activity, FAPI tracer uptake, and causal biological function. We summarize its membrane topology, dimerization, catalytic pocket, dipeptidyl peptidase and endopeptidase activities, and structural basis for selective targeting within the S9B serine protease subfamily. We discuss chronic liver injury-induced FAPα-positive HSC programs, extracellular matrix (ECM) remodeling, integrin-mediated mechanotransduction, and macrophage-stromal inflammatory amplification. At the fibrosis-cirrhosis-HCC interface, FAPα-positive CAF states are associated with, and in selected experimental models contribute to, spatial tumor architecture, immune exclusion, and therapeutic resistance. We further evaluate tissue profiling, investigational FAPα-responsive magnetic resonance imaging (MRI), early-clinical fibroblast activation protein inhibitor (FAPI)-based positron emission tomography (PET), fluorescence-guided surgery, direct enzymatic inhibition, FAPα/integrin co-targeting, protease-activated prodrugs, targeted nanomedicine, radioligand theranostics, anti-FAP cellular therapy, and combinations with immunotherapy or anti-angiogenic treatment. Collectively, FAPα is an evidence-stage-dependent stromal target for mechanistic stratification, molecular imaging, and therapeutic development; prevention of HCC and reduction of recurrence remain hypotheses requiring prospective validation.