FGFR2 Regulates Liver Injury and Repair in a Model of Obstructive Jaundice.

BACKGROUND

The molecular mechanisms underlying obstructive jaundice (OJ)-induced liver injury and subsequent repair after biliary recanalization (R-OJ) remain incompletely elucidated. This study aimed to identify and validate core gene involved in regulating OJ-related liver injury and repair via integrated in vitro and in vivo models.

METHODS

Animal models (OJ and R-OJ groups) and cell models (OJ serum (OJS) and OJ serum depletion (OJSD) groups) were established. Liver function and histopathologic changes were evaluated. Differentially expressed genes (DEGs) were screened by RNA sequencing (RNA-seq), and candidate genes were selected by intersecting DEGs with functional gene sets associated with "injury" and "repair". Key genes were identified via protein-protein interaction (PPI) network and pathway enrichment analyses. Fibroblast growth factor receptor 2 (FGFR2) expression was validated by quantitative reverse transcription PCR (qRT-PCR), Western blot, and immunohistochemistry (IHC). Functional involvement of FGFR2 was assessed by siRNA-mediated knockdown followed by assessment of downstream AKT signaling, proliferation (proliferating cell nuclear antigen, PCNA), and apoptosis maker cleaved caspase-3.

RESULTS

OJ induced significant liver dysfunction and tissue damage, which partially recovered after R-OJ. Bioinformatic analyses identified FGFR2 as a core regulatory gene among 20 candidates. FGFR2 was downregulated during injury (OJS vs. Con, p < 0.05) and upregulated during repair (OJSD vs. OJS, p < 0.05) both in vivo and in vitro. FGFR2 knockdown in BRL-3A cells markedly reduced p-AKT levels by approximately 50% under all serum conditions (p < 0.01), significantly decreased PCNA expression, and altered cleaved caspase-3 levels, suggesting that FGFR2 may contribute to hepatocyte proliferation and survival, potentially through the phosphoinositide 3-kinase (PI3K)/AKT signaling.

CONCLUSION

FGFR2 exhibits a dynamic expression pattern of downregulation during cholestatic injury and upregulation during repair, and is associated with hepatocyte proliferation and apoptosis, potentially through AKT signaling. These findings suggest that FGFR2 may represent a potential therapeutic target for improving liver repair in obstructive jaundice.