{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T11:56:13Z","timestamp":1790942173307,"version":"4.1.0"},"reference-count":35,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T00:00:00Z","timestamp":1775001600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["R01DK126875"],"award-info":[{"award-number":["R01DK126875"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,4,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Deficiency of ferrochelatase (FECH) in erythropoietic protoporphyria (EPP) leads to accumulation of its substrate, protoporphyrin IX (PPIX), the final intermediate in the heme biosynthesis pathway. PPIX is produced primarily in the bone marrow and subsequently delivered to the liver, where it can cause cholestatic liver injury and, in severe cases, liver failure. A key unresolved question is how circulating PPIX is transported to the liver to initiate hepatic damage. Given the structural similarity between PPIX and heme, we investigated whether the heme carrier hemopexin (HPX) mediates this process. Using an EPP mouse model carrying a Fech mutation (Fech-mut), we generated mice additionally lacking Hpx (Fech-mut\/Hpx-null). As expected, Fech-mut mice exhibited markedly elevated PPIX levels in both the circulation and liver. However, Hpx deficiency did not alter PPIX distribution in Fech-mut\/Hpx-null mice, indicating that HPX is not required for the delivery of circulating PPIX to the liver. Similarly, Hpx deficiency did not modify the severity of PPIX-induced cholestatic liver injury. Computational modeling further revealed that PPIX\u2013HPX binding is energetically unfavorable, making HPX-mediated uptake unlikely. In summary, HPX does not contribute to hepatic PPIX uptake or influence cholestatic liver injury in EPP. These findings redirect attention to alternative hepatic uptake mechanisms and underscore the need to define the pathways that modulate PPIX delivery to the liver and shape susceptibility to EPP-associated liver injury.<\/jats:p>","DOI":"10.1093\/toxsci\/kfag041","type":"journal-article","created":{"date-parts":[[2026,4,4]],"date-time":"2026-04-04T11:38:09Z","timestamp":1775302689000},"source":"Crossref","is-referenced-by-count":0,"title":["Role of hemopexin in protoporphyrin IX distribution and cholestatic liver injury"],"prefix":"10.1093","volume":"209","author":[{"given":"Ruizhi","family":"Gu","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Sciences, School of Pharmacy, Center for Pharmacogenetics, University of Pittsburgh , Pittsburgh, PA, 15213,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fu-Ying","family":"Qin","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, School of Pharmacy, Center for Pharmacogenetics, University of Pittsburgh , Pittsburgh, PA, 15213,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zeyu","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, School of Pharmacy, Center for Pharmacogenetics, University of Pittsburgh , Pittsburgh, PA, 15213,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xujian","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, School of Pharmacy, Computational Chemical Genomics Screening Center, University of Pittsburgh , Pittsburgh, PA, 15213,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elim","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, School of Pharmacy, Center for Pharmacogenetics, University of Pittsburgh , Pittsburgh, PA, 15213,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, School of Pharmacy, Center for Pharmacogenetics, University of Pittsburgh , Pittsburgh, PA, 15213,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9607-8229","authenticated-orcid":false,"given":"Junmei","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, School of Pharmacy, Computational Chemical Genomics Screening Center, University of Pittsburgh , Pittsburgh, PA, 15213,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaochao","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, School of Pharmacy, Center for Pharmacogenetics, University of Pittsburgh , Pittsburgh, PA, 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