FGFR1-FGFR4 remodeling drives PLCγ-Ca 2+ -dependent hepatic stellate cell activation in liver fibrosis
Year: 2026
Type: article
Abstract: Hepatic fibrosis is a maladaptive wound-healing response driven by chronic liver injury and sustained activation of hepatic stellate cells (HSCs).Although fibroblast growth factor receptor (FGFR) signaling is essential for liver metabolism and regeneration, how individual FGFR isoforms are reorganized during fibrogenesis and contribute to HSC activation remains incompletely understood.Here, we integrated whole-liver transcriptomic meta-analysis, in vivo fibrosis models, singlenucleus RNA sequencing, and functional studies in human HSCs to define FGFR remodeling in hepatic fibrosis.While bulk transcriptomics revealed isoform-specific changes in FGFR expression, single-nucleus analysis uncovered a dynamic spatiotemporal redistribution: FGFR1 remained stably enriched in stellate cells, whereas FGFR4 shifted from hepatocyte-dominant expression in healthy liver to inducible acquisition by activated HSCs during advanced fibrosis.Functional studies in human LX-2 cells demonstrated that FGFR4 is dynamically induced during HSC activation, whereas FGFR1 remains abundantly and stably expressed.This activation-associated FGFR remodeling selectively reprogrammed downstream signaling, marked by enhanced phospholipase Cγ (PLCγ) activation and increased basal Ca 2+ influx.Chelating extracellular Ca 2+ or pharmacological inhibition of FGFR or PLCγ attenuated Ca 2+ entry and reduced fibrogenic marker expression, establishing sustained Ca 2+ influx as a functional requirement for maintaining the activated HSC phenotype.Together, these findings identify a previously unrecognized FGFR4-PLCγ-Ca 2+ signaling axis that sustains HSC activation and redefines FGFR4 as an activation-dependent regulator in hepatic fibrosis.
DOI: 10.4196/kjpp.26.024
Institution: Yonsei University
Language: English
Subfield: Hepatology
Field: Medicine
Domain: Health Sciences
Open Access status: diamond
OpenAlex ID: W7170109190