{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:58:47Z","timestamp":1787029127884,"version":"build-2736575974"},"reference-count":80,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T00:00:00Z","timestamp":1779148800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100006827","name":"FLDOH","doi-asserted-by":"crossref","award":["#268"],"award-info":[{"award-number":["#268"]}],"id":[{"id":"10.13039\/100006827","id-type":"DOI","asserted-by":"crossref"}]},{"name":"NIH","award":["# 2R01AI132711-06"],"award-info":[{"award-number":["# 2R01AI132711-06"]}]},{"award":["# 2R01AI132711-06"],"award-info":[{"award-number":["# 2R01AI132711-06"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"name":"the USF Provost\u2019s CREATE Award","award":["FY24\u201327"],"award-info":[{"award-number":["FY24\u201327"]}]},{"name":"the COPH Research Award"},{"name":"WLP award","award":["FY2023"],"award-info":[{"award-number":["FY2023"]}]},{"name":"the USF Microbiome Institute Award"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Heme metabolism in the liver has traditionally been described as a linear pathway that supports oxygen utilization, redox balance, and detoxification. Here, we synthesize recent evidence and propose a framework in which heme functions as a system-level regulator, the \u201cqueen\u201d of metabolism, whereas its upstream intermediate protoporphyrin IX (PPIX) represents a chemically reactive \u201cdark twin\u201d that emerges when metabolic flux fails to resolve. In this view, metabolic state is defined not only by end products but also by the behavior of pathway intermediates. This system is spatially organized. Hepatocytes dominate heme synthesis and utilization. In contrast, liver stromal compartments, particularly Kupffer cells, play a central role in heme degradation through heme oxygenase-1 (HMOX1), linking heme turnover to iron recycling and stress adaptation. The metabolic state of the liver therefore reflects not only pathway flux but also the degree of coupling between these cellular compartments. We propose a state model of hepatic heme metabolism. In the resolution state, most evident during inflammation, coordinated hepatocyte\u2013macrophage activity maintains flux and limits intermediate accumulation. In contrast, the expansion state, exemplified in cancer, is defined by impaired flux completion, leading to PPIX accumulation, metabolic heterogeneity, and oxidative stress. This framework reframes liver disease through intermediate behavior rather than pathway presence: porphyrias reflect direct overload, metabolic liver diseases partial expansion, and hepatocellular carcinoma a fully developed expansion state. By focusing on the \u201cintermediate space,\u201d this model links biochemistry, spatial organization, and disease pathogenesis, while suggesting new opportunities for diagnosis and therapy based on metabolic state.<\/jats:p>","DOI":"10.3390\/molecules31101719","type":"journal-article","created":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T07:35:43Z","timestamp":1779176143000},"page":"1719","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["The Queen and the Dark Twin: Heme, Protoporphyrin IX, and State Transitions in Liver Metabolism"],"prefix":"10.3390","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3313-2782","authenticated-orcid":false,"given":"Swamy R.","family":"Adapa","sequence":"first","affiliation":[{"name":"Department of Global, Environmental, and Genomic Health Sciences, College of Public Health, University of South Florida, Tampa, FL 33612, USA"},{"name":"Genomics Program, University of South Florida, Tampa, FL 33612, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8982-4169","authenticated-orcid":false,"given":"Rays H. Y.","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Global, Environmental, and Genomic Health Sciences, College of Public Health, University of South Florida, Tampa, FL 33612, USA"},{"name":"Genomics Program, University of South Florida, Tampa, FL 33612, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Pinna, S., Kunz, C., Halpern, A., Harrison, S.A., Jordan, S.F., Ward, J., Werner, F., and Lane, N. (2022). A prebiotic basis for ATP as the universal energy currency. PLoS Biol., 20.","DOI":"10.1371\/journal.pbio.3001437"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1038\/s41392-020-00311-7","article-title":"NAD(+) metabolism: Pathophysiologic mechanisms and therapeutic potential","volume":"5","author":"Xie","year":"2020","journal-title":"Signal Transduct. Target. 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