Introduction: Cirrhosis patients exhibit cytopenia and variable response to GCSF, with benefits in early cirrhosis. GCSF acts through the CSF3-receptor (CSF3R), and changes in CSF3R can affect the response. We investigated the possible mechanism for the lack of efficacy of GCSF in advanced cirrhosisMethodsCirrhotic patients (n = 127) and controls (n = 26) who underwent clinically indicated bone marrow (BM) examination were studied. BMs were assessed for RNA sequencing, qRT-PCR, and immunohistochemistry (IHC) for CSF3R and associated genes. Circulating GCSF, CSF3R, and carcinoembryonic antigen cell adhesion molecule-1 (CEACAM1) were measured. BM hematopoietic precursor cells and their alterations were examined by flow cytometry. The findings were validated, where the GCSF was administered as for liver regeneration (n = 22) and severe neutropenia (n = 15)ResultsThe mean age was 48.6 ± 13.4 years, 80.3% males. Gene set enrichment analysis showed lowered CSF3R in Child's C compared to A, confirmed by qRT-PCR and IHC. Circulatory CSF3R was also reduced in advanced cirrhosis. CSF3R decline was related to decrease hematopoietic stem cells (HSCs) and downregulation of CSF3R in remaining HSCs. CSF3R inhibitory protein CEACAM1 caused CSF3R downregulation. CEACAM-1, in turn, positively correlated with the increased lysosomal expression in HSCs. Peripheral blood-CSF3R was lesser in those cases who developed an infection Baseline CSF3R was also lower in G-CSF non-responders.ConclusionsCSF3R is downregulated in patients with advanced cirrhosis, and it could be the underlying cause of the inadequate response to GCSF.