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In response to primary liver disease, the abnormal adaptation of respiratory epithelial cells, pulmonary endothelial cells and immune cells leads to pulmonary microenvironment disequilibrium and HPS. In this review, we explore the pathophysiologic mechanisms of HPS, including vascular dilation, angiogenesis and alveolar dysfunction. The liver is the primary contributor to HPS, and liver transplantation is the only treatment that generally reverses HPS. We then discuss how disruption of hepatic sinusoidal homeostasis may impact the progression of HPS, mainly focusing on hepatocytes, cholangiocytes, LSECs and macrophages. As HPS occurs more commonly in advanced liver cirrhosis, we also discuss that normalisation of liver dysfunction and portal hypertension is crucial for the resolution of HPS. In conclusion, liver\u2010targeted therapies may be effective in treating HPS.<\/jats:p>","DOI":"10.1111\/jcmm.70585","type":"journal-article","created":{"date-parts":[[2025,5,8]],"date-time":"2025-05-08T23:24:47Z","timestamp":1746746687000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Disruption of Hepatic Sinusoidal Homeostasis Leads to Hepatopulmonary Syndrome"],"prefix":"10.1111","volume":"29","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-0449-0009","authenticated-orcid":false,"given":"Jiaxin","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Gastroenterology, Lab of Gastroenterology and Hepatology West China Hospital, Sichuan University  Chengdu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yangkun","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Lab of Gastroenterology and Hepatology West China Hospital, 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