{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T23:28:23Z","timestamp":1788305303772,"version":"build-2803163510"},"reference-count":105,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2026,4,3]],"date-time":"2026-04-03T00:00:00Z","timestamp":1775174400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>Although the molecular pathogenesis of bilirubin-induced neuronal cell injury is not completely understood, certain recurrent themes resonate in the literature on this topic and include the generally untoward effects of high unconjugated bilirubin (UCB) concentrations on membranes (plasma, mitochondrial, and endoplasmic reticulum (ER)), cellular bioenergetics, and intracellular calcium homeostasis. Only in the last decade, ER was discovered as an early target of bilirubin neurotoxicity. We will review the main features of bilirubin neurotoxicity from the point of view of ER and bilirubin-induced ER stress. Neuronal excitotoxicity, mitochondrial energy failure, and increased intracellular calcium concentration are three phenomena linked spatially and temporally in the pathogenesis of bilirubin-induced neurotoxicity. ER, being the main intracellular calcium storage organelle, is involved in the increase in the universal second messenger, calcium. This event leads to the activation of proteolytic enzymes, apoptotic pathways, and necrosis, the occurrence of which is likely a function of the degree and duration of bilirubin exposure.<\/jats:p>","DOI":"10.3390\/antiox15040451","type":"journal-article","created":{"date-parts":[[2026,4,6]],"date-time":"2026-04-06T03:11:28Z","timestamp":1775445088000},"page":"451","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["The Role of ER Stress in Bilirubin Neurotoxicity: A Complex Molecular Network"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-9965-8041","authenticated-orcid":false,"given":"Mohammed","family":"Qaisiya","sequence":"first","affiliation":[{"name":"Innovative Models Unit, Fondazione Italiana Fegato (Italian Liver Foundation), 34149 Trieste, Italy"},{"name":"Department of Medical Laboratory Science, Hebron University, Hebron  P785, Palestine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6596-7595","authenticated-orcid":false,"given":"Claudio","family":"Tiribelli","sequence":"additional","affiliation":[{"name":"Innovative Models Unit, Fondazione Italiana Fegato (Italian Liver Foundation), 34149 Trieste, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2865-2575","authenticated-orcid":false,"given":"Cristina","family":"Bellarosa","sequence":"additional","affiliation":[{"name":"Innovative Models Unit, Fondazione Italiana Fegato (Italian Liver Foundation), 34149 Trieste, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"149472","DOI":"10.1016\/j.brainres.2025.149472","article-title":"Unraveling the Dual Role of Bilirubin in Neurological Diseases: A Comprehensive Exploration of Its Neuroprotective and Neurotoxic Effects","volume":"1851","author":"Kaur","year":"2025","journal-title":"Brain Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"10852","DOI":"10.1074\/jbc.274.16.10852","article-title":"Unconjugated Bilirubin Exhibits Spontaneous Diffusion through Model Lipid Bilayers and Native Hepatocyte Membranes","volume":"274","author":"Zucker","year":"1999","journal-title":"J. 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