{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nThe ATP‐binding cassette transporter ABCB11 encodes the bile salt export pump (BSEP), an ATP‐dependent protein localized at the hepatocyte canalicular membrane that is essential for the active secretion of bile acids into bile. This process is a rate‐limiting step in bile formation and in maintaining bile acid homeostasis. ABCB11 expression is tightly regulated by several nuclear receptors and transcription factors—including farnesoid X receptor (FXR), liver receptor homolog‐1 (LRH‐1), and nuclear factor erythroid 2–related factor 2 (Nrf2)—which, in response to endogenous bile acids and other ligands, coordinate both the transcriptional activation and chromatin modifications necessary for proper bile acid handling."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "4"}]}, {"type": "t", "text": "\n\nThe function of ABCB11 is clinically underscored by the observation that genetic mutations, splicing defects, and common polymorphisms impacting its expression or trafficking lead to a spectrum of cholestatic liver diseases. Loss‐of‐function mutations or misprocessing of BSEP (for example, through aberrant splicing or defective post-translational modification such as seen with the D482G and E297G variants) are associated with conditions like progressive familial intrahepatic cholestasis type 2 (PFIC2), benign recurrent intrahepatic cholestasis (BRIC2), intrahepatic cholestasis of pregnancy (ICP), and even pediatric hepatocellular carcinoma in the setting of canalicular transporter deficiency. These studies demonstrate that disease severity often correlates with the degree of residual BSEP expression observed by immunohistochemistry or its plasma membrane localization."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "5", "end_ref": "18"}]}, {"type": "t", "text": "\n\nFurthermore, altered regulation and genetic variability of ABCB11 not only predispose individuals to inherited cholestatic disorders but also contribute to drug-induced liver injury through impaired bile acid disposition. Studies in both human and animal hepatocyte models reveal that chemical inhibition or down-regulation of BSEP, in combination with other factors, results in intracellular bile acid accumulation and subsequent hepatocellular injury. Population-based analyses and functional characterizations have identified additional variants and regulatory polymorphisms that modulate the transporter’s expression, further influencing susceptibility to cholestasis in contexts such as pregnancy, chronic viral hepatitis, and non-alcoholic fatty liver disease. Collectively, these findings exemplify the central role of ABCB11 in controlling biliary bile acid secretion, with disturbances in its function or regulation producing a broad array of pathophysiological consequences."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "19", "end_ref": "38"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Nicole Soranzo, Serena Sanna, Eleanor Wheeler, et al. 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