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Background Biallelic mutations in humans ABCB4 causes MDR3 deficiency which manifests as progressive familial intrahepatic cholestasis (PFIC) type 3. In mice, deletion of Abcb4 causes Mdr2 deficiency (Mdr2-/-); these mice develop chronic liver injury, progressing to biliary fibrosis. They are used to study primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC) and intrahepatic cholestasis. However, there has been no systematic assessment of how these mice respond therapeutically. A better understanding of this could provide insights into how effectively this model recapitulates human pathology.Aim We performed a systematic review and meta-analysis of published studies which used Mdr2-/- mice to investigate the effect of different therapies in cholestatic liver disease.Methods We searched PubMed, GoogleScholar, and MEDLINE (from inception to February 2024) for studies that used Mdr2-/- mice to assess the effect of therapeutic interventions. Four categories with the most studies were selected for further analysis: bile acid analogues (BAAs e.g. ursodeoxycholic acid), farnesoid X receptor (FXR) agonists (e.g. obeticholic acid), fibroblast growth factor 19 (FGF19) analogues, and apical sodium-dependent bile acid transporter (ASBT) inhibitors (e.g. Maralixibat). Outcomes were serum ALT and total bilirubin, bile duct proliferation (measured by immunohistochemical CK19 levels) and fibrosis (measured by immunohistochemical COL1A1 levels or Ishak fibrosis score). Random effects meta-analysis was performed throughout.Results 666 studies were screened. 109 studies underwent full-text review. Data was extracted from 88 studies, including 20 studies on BAAs (n=8), FXR agonists (n=5), FGF19 analogues (n=4) and ASBT inhibitors (n=3).BAAs were not associated with significant improvements of any of the assessed outcomes, similar to patients with severe protein truncating mutations in ABCB4 and patients with PSC. FXR agonists were associated with significant reductions in: bilirubin (p=.01), COL1A1 levels, and Ishak fibrosis score (p<.0001), though with substantial inter-study heterogeneity (I2=82%). These drugs are known to improve biochemistry in patients with PBC and have positive data in in phase 2B studies in PSC. FGF19 analogues were only associated with a reduction in Ishak fibrosis score (p=.03). ASBT inhibitors were associated with a strongly statistically significant reduction in ALT (p=1.2x10-21) with minimal heterogeneity (I2=5.1%), though there was insufficient studies for other outcomes. ASBT inhibitors improve liver biochemistry and transplant-free survival in patients with PFIC.All outcomes were strongly affected by publication bias (Egger’s test p<1x10-4) except bilirubin.Conclusions Mdr2-/- mice show a limited response to BAAs (including ursodeoxycholic acid), consistent with humans who have severe loss-of-function ABCB4 mutations and PSC but not PBC. Mdr2-/- mice appear to respond to modulation of other bile acid pathways (i.e. FGF19 and FXR); this is consistent with PBC and PSC and has not yet been extensively studied in PFIC. The data is heavily skewed by publication bias, except for bilirubin. With this in mind, Mdr2-/- mice effectively model severe ABCB4 deficiency in humans, but have variable overlap with phenotype of PBC and PSC.Abstract OC36 Figure 1