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Bilirubin: Health Challenges and Opportunities
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Bilirubin: Health Challenges and Opportunities

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: 20 September 2025 | Viewed by 2845

Special Issue Editor

Dr. Silvia Gazzin

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Guest Editor
Fondazione Italiana Fegato-Onlus, Basovizza, Trieste, Italy
Interests: neuroinflammation; homocysteine in neurology

Special Issue Information

Dear Colleagues,

For a long time now, bilirubin has been considered more than a mere waste metabolite of hemoglobin. Bilirubin is a hormone, a regulator of various signaling pathways, and an endogenous protection factor from redox stress and inflammation, and it helps against diseases of the advanced age and might improve performance in athletes. Evaluations to assess its potential as an antibacterial agent, as well as its use in anti-inflammatory, antioxidant, and neurologic nanotechnology applications is ongoing. On the other hand, the knowledge on its pathomolecular mechanism involved in brain damage in Crigler–Najjar syndrome and in neonatal hyperbilirubinemia is expanding. The golden standard therapy (phototherapy) seems inefficient in pre-term neonates, and severe hyperbilirubinemia persists as a major cause of neonatal death in different parts of the world, requiring commitment to develop innovative studies and therapeutic approaches.

Therefore, advancing the understanding on the molecular functions of this pigment and of the enzymes involved in its metabolism (the yellow players) and biological function is crucial and is not only a never ending need for human health but also a new challenge for its technological uses.

Papers aimed at exploring these aspects of the yellow players are welcome.

Dr. Silvia Gazzin
Guest Editor

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Keywords

  • bilirubin
  • biomedical science
  • neurobiology
  • Parkinson’s disease
  • brain neuroprotection

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Published Papers (3 papers)

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35 pages, 5871 KiB  
Article
Transcriptomic and Proteomic Changes in the Brain Along with Increasing Phenotypic Severity in a Rat Model of Neonatal Hyperbilirubinemia
by John Paul Llido, Giorgia Valerio, David Křepelka, Aleš Dvořák, Cristina Bottin, Fabrizio Zanconati, Julia Theresa Regalado, Audrey Franceschi Biagioni, Mohammed Qaisiya, Libor Vítek, Claudio Tiribelli and Silvia Gazzin
Int. J. Mol. Sci. 2025, 26(13), 6262; https://doi.org/10.3390/ijms26136262 - 28 Jun 2025
Viewed by 553
Abstract
Kernicterus spectrum disorder is the permanent and highly disabling neurologic sequel of neonatal exposure to hyperbilirubinemia, presenting, among other symptoms, variable and untreatable motor disabilities. To search for potential biomolecular explanations, we used a Gunn rat colony exhibiting spontaneous hyperbilirubinemia and a large [...] Read more.
Kernicterus spectrum disorder is the permanent and highly disabling neurologic sequel of neonatal exposure to hyperbilirubinemia, presenting, among other symptoms, variable and untreatable motor disabilities. To search for potential biomolecular explanations, we used a Gunn rat colony exhibiting spontaneous hyperbilirubinemia and a large variability of motor deficits on a beam-walking test. Histological and microscopic analyses confirmed worsening damage in the cerebellum (Cll; hypoplasia, increased death of neurons, and disrupted astroglial structures) and parietal motor cortex (hCtx; increased cell sufferance and astrogliosis). Clustering and network analyses of transcriptomic data reveal rearrangement of the physiological expression patterns and signaling pathways associated with bilirubin neurotoxicity. Bilirubin content among hyperbilirubinemic (jj) animals is overlapped, which suggests that the amount of bilirubin challenge does not fully explain the tissue, transcriptomic, proteomic, and neurobehavioral alterations. The expression of nine genes involved in key postnatal brain development processes is permanently altered in a phenotype-dependent manner. Among them, Grm1, a metabotropic glutamatergic receptor involved in glutamate neurotoxicity, is consistently downregulated in both brain regions both at the transcriptomic and proteomic levels. Our results support the role of Grm1 and glutamate as biomolecular markers of ongoing bilirubin neurotoxicity, suggesting the possibility to improve diagnosis by 1H-MR spectroscopy. Full article
(This article belongs to the Special Issue Bilirubin: Health Challenges and Opportunities)
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14 pages, 289 KiB  
Article
Circulating Bilirubin Levels, but Not Their Genetic Determinants, Are Inversely Associated with Steatotic Liver Disease in Adolescents
by José Patricio Miranda, Juan Cristóbal Gana, Gigliola Alberti, Karen Galindo, Ana Pereira and José Luis Santos
Int. J. Mol. Sci. 2025, 26(7), 2980; https://doi.org/10.3390/ijms26072980 - 25 Mar 2025
Viewed by 498
Abstract
Epidemiologic studies suggest that elevated plasma unconjugated bilirubin confer protection against steatotic liver disease (SLD) in adults. However, evidence supporting this protective role in adolescents remains limited. We aimed to assess the association between serum bilirubin levels and their genetic determinants in protecting [...] Read more.
Epidemiologic studies suggest that elevated plasma unconjugated bilirubin confer protection against steatotic liver disease (SLD) in adults. However, evidence supporting this protective role in adolescents remains limited. We aimed to assess the association between serum bilirubin levels and their genetic determinants in protecting against SLD in Chilean adolescents. We conducted a cross-sectional study with 704 adolescents aged 15.4 ± 1 years (52% girls) of the Chilean Growth and Obesity Cohort Study. Ultrasonography echogenicity was used to diagnose SLD. We measured Z-scores of body mass index (z-BMI), total bilirubin (TB), and the genetic determinants of bilirubin (including rs887829 genotypes of UGT1A1 and bilirubin polygenic scores). Multiple logistic regression models evaluated the associations between standardized TB and its genetic determinants with SLD. We found that 1-SD of standardized plasma TB was significantly associated with a 30% reduction in the likelihood of SLD after adjustment by sex, age, z-BMI, and ethnicity (OR = 0.7; 95% CI = 0.50–0.96; p = 0.03). No significant associations were found among the rs887829 genotypes, bilirubin polygenic scores, and SLD in logistic regression models adjusted by covariates. Increased circulating bilirubin levels are unlikely causally associated with protection against SLD, and the cross-sectional association could be due to unmeasured confounding. Full article
(This article belongs to the Special Issue Bilirubin: Health Challenges and Opportunities)

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9 pages, 964 KiB  
Brief Report
Bilirubin Metabolism Does Not Influence Serum Bile Acid Profiles According to LC–MS: A Human Case-Control Study
by Tamara Christina Stelzer, Ralf Krüger, Paola Gloria Ferrario, Christine Mölzer, Marlies Wallner, Rodrig Marculescu, Daniel Doberer, Andrew Cameron Bulmer and Karl-Heinz Wagner
Int. J. Mol. Sci. 2025, 26(6), 2475; https://doi.org/10.3390/ijms26062475 - 10 Mar 2025
Viewed by 861
Abstract
In addition to their role in lipid absorption, bile acids (BAs) are also known for several relevant (endocrine) activities including contributing to the regulation of energy homeostasis and some non-communicable diseases (NCDs). Furthermore, moderately elevated unconjugated bilirubin levels, as observed in Gilbert’s syndrome [...] Read more.
In addition to their role in lipid absorption, bile acids (BAs) are also known for several relevant (endocrine) activities including contributing to the regulation of energy homeostasis and some non-communicable diseases (NCDs). Furthermore, moderately elevated unconjugated bilirubin levels, as observed in Gilbert’s syndrome (GS), may protect against NCDs. We therefore hypothesized that the BA profile in GS subjects differs from that of normo-bilirubinemic individuals. To test this, we performed a human case-control study, in which GS (n = 60) and controls (n = 60) were matched for age and gender, and serum BA concentrations were measured by liquid-chromatography mass spectrometry (LC–MS). Despite analyzing a comprehensive panel of BAs, no significant differences between the two groups were observed. These data suggest that bile acid concentrations are similar between groups, indicating that altered bilirubin metabolism unlikely influences their transport into the blood. Full article
(This article belongs to the Special Issue Bilirubin: Health Challenges and Opportunities)
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