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The Heme Oxygenase/Biliverdin Reductase System in Human Health and Disease:...
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The Heme Oxygenase/Biliverdin Reductase System in Human Health and Disease: New Molecular Insights and Therapeutic Targets

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Molecular Medicine".

Deadline for manuscript submissions: 1 September 2026 | Viewed by 2838

Special Issue Editor

Prof. Dr. Cesare Mancuso

E-Mail Website
Guest Editor
1. Facoltà di Medicina e Chirurgia, Università Cattolica del Sacro Cuore, Rome, Italy
2. Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
Interests: Alzheimer’s disease; gasotransmitters; neuropeptides; oxidative/nitrosative stress; pharmacology; polyphenols

Special Issue Information

Dear Colleagues,

Heme oxygenase (HO) catalyzes the breakdown of heme into ferrous iron, carbon monoxide (CO), and biliverdin-IXα (BV), which is subsequently converted into bilirubin-IXα (BR) by biliverdin reductase-A (BVR). Two HO isoforms exist: HO-1, an inducible enzyme, and HO-2, which is constitutively expressed. HO-1 is strongly upregulated by free radicals and pro-inflammatory signals, reducing intracellular heme—a cytotoxic molecule under redox imbalance—and generating CO, a gaseous neuromodulator with cytoprotective functions. These properties have placed HO-1 at the center of intense research over recent decades.

Preclinical studies consistently associate HO-1 with neurological disorders, including Alzheimer’s disease, Parkinson’s disease, and cerebral malaria, as well as cardiovascular, renal, metabolic diseases and cancer. Furthermore, many xenobiotics induce HO-1 and elicit protective effects, making this isoform an attractive target in drug R&D. In contrast, HO-2 research has progressed more slowly. Its role as a basal regulator of heme turnover and the limited evidence for its involvement in gaseous molecule sensing have limited interest in HO-2 clinical exploitation. BVR, once viewed merely as the enzyme producing BR, experienced renewed attention in the 2000s, when additional tyrosine and serine/threonine kinase functions were identified. Today, BVR is recognized as an important regulator of glucose metabolism, neurodegeneration, and immune responses.

This Special Issue of Biomolecules welcomes contributions exploring the HO/BVR system in health and disease, including new mechanistic insights and therapeutic opportunities.

Prof. Dr. Cesare Mancuso
Guest Editor

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Alzheimer’s disease
  • bilirubin
  • cancer
  • carbon monoxide
  • cardiovascular diseases
  • cerebral malaria
  • diabetes mellitus
  • drug research and development
  • inflammation
  • Parkinson’s disease

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Published Papers (4 papers)

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Research

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14 pages, 1211 KB  
Article
Predominance of Biliverdin over Bilirubin in Human Seminal Plasma
by Nina Hojnik, Paola Sist, Sabina Passamonti, Borut Kovačič and Federica Tramer
Biomolecules 2026, 16(4), 569; https://doi.org/10.3390/biom16040569 - 11 Apr 2026
Viewed by 447
Abstract
Biliverdin (BV) and bilirubin (BR) are established endogenous antioxidants and immune modulators in other organ systems; however, their roles in the male genital tract remain undefined. The aim of this study was to quantify both bile pigments in human seminal plasma using a [...] Read more.
Biliverdin (BV) and bilirubin (BR) are established endogenous antioxidants and immune modulators in other organ systems; however, their roles in the male genital tract remain undefined. The aim of this study was to quantify both bile pigments in human seminal plasma using a fluorescent protein biosensor and to examine their associations with basic semen parameters. We analyzed forty-two semen samples from men undergoing infertility evaluation. Biliverdin predominated over bilirubin in 88.1% of samples. Biliverdin concentration ranged from 51.8 to 611.2 nM, whereas bilirubin ranged from 19.7 to 240.7 nM. The mean total amounts per ejaculate were 1054 pmol for biliverdin and 280 pmol for bilirubin. The total amount of bilirubin in the ejaculate was positively correlated with total sperm count (Rs = 0.47; p = 0.028), whereas biliverdin showed no significant association (Rs = 0.21; p = 0.723). Oligozoospermic samples had significantly lower bilirubin concentrations (p < 0.001) and lower total bilirubin amounts (p < 0.005). Teratozoospermic samples exhibited significantly higher biliverdin concentrations (p < 0.05). This study provides the first simultaneous quantification of biliverdin and unconjugated bilirubin in human seminal plasma and identifies distinct associations with sperm quality. These findings suggest that bile pigments may reflect localized redox-related processes in the male genital tract and may influence male fertility potential. Full article
(This article belongs to the Special Issue The Heme Oxygenase/Biliverdin Reductase System in Human Health and Disease: New Molecular Insights and Therapeutic Targets)
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20 pages, 2869 KB  
Article
Behavior and Musculoskeletal Effects of Chronic D-Galactose Treatment in Mice: Role of Heme Oxygenase-1
by Sally Wahba, Olufunto O. Badmus, Andrew R. Wasson, Elshymaa A. Abdel-Hakeem, Merhan Mamdouh Ragy, Hanaa Mohamad Ibrahim, Daniela Rüedi-Bettschen and David E. Stec
Biomolecules 2026, 16(4), 548; https://doi.org/10.3390/biom16040548 - 8 Apr 2026
Viewed by 526
Abstract
Chronic d-galactose (d-gal) treatment is a model to induce accelerated aging-like phenotypes in rodents. However, the sex differences in behavioral and musculoskeletal manifestations of this model are not well understood. Heme oxygenase-1 (HO-1) is a cytoprotective protein that may have anti-aging properties. The [...] Read more.
Chronic d-galactose (d-gal) treatment is a model to induce accelerated aging-like phenotypes in rodents. However, the sex differences in behavioral and musculoskeletal manifestations of this model are not well understood. Heme oxygenase-1 (HO-1) is a cytoprotective protein that may have anti-aging properties. The goal of this study was to better understand the sex differences in the behavioral and musculoskeletal effects of chronic d-gal treatment in C57BL/6J mice, as well as the role of HO-1 induction or inhibition. Eight-week-old male and female mice received daily saline or d-gal injections (500 mg/kg, s.c.) for 12 weeks. After this time, mice in the d-gal group were randomized into three groups (n = 6/group/sex): d-gal, d-gal + cobalt protoporphyrin (CoPP) (5 mg/kg, s.c. weekly), and d-gal + zinc deutroporphyrin bisglycol (ZnBG) (42 mg/kg, i.p. triweekly) for a period of 4 weeks. Open-field, novel-object recognition, Barnes maze, grip strength, micro-computed tomography (µ-CT), histology, and protein analysis were performed. Chronic d-gal treatment resulted in a sexual dimorphic response, with female mice being more prone to develop deficits in both short- and long-term spatial memory as well as in non-spatial memory. Male mice exhibited deficits only in long-term spatial memory when treated chronically with d-gal. Inhibition of HO-1 was protective in both females and males. Chronic d-gal treatment did not accelerate the development of osteoporosis or sarcopenia in either males or females. Our results demonstrate a sexual dimorphic response to the chronic effects of d-gal treatment on aging, with greater effects in females than in males, which is dependent on HO-1. Full article
(This article belongs to the Special Issue The Heme Oxygenase/Biliverdin Reductase System in Human Health and Disease: New Molecular Insights and Therapeutic Targets)
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Review

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26 pages, 2350 KB  
Review
Transforming Toxicity into Therapy: Exploring Bilirubin’s Benefits and Its Molecular Role in Cardiac Health and Disease
by Michael I. Adenawoola, Zachary A. Kipp, Terry D. Hinds, Jr. and David E. Stec
Biomolecules 2026, 16(5), 625; https://doi.org/10.3390/biom16050625 - 23 Apr 2026
Viewed by 637
Abstract
Bilirubin, historically recognized solely as a waste product of heme catabolism, has recently gained attention for its potential protective role in the cardiovascular system. Experimental and clinical studies suggest that bilirubin exhibits potent antioxidant, anti-inflammatory, anti-apoptotic, and cytoprotective properties that may protect the [...] Read more.
Bilirubin, historically recognized solely as a waste product of heme catabolism, has recently gained attention for its potential protective role in the cardiovascular system. Experimental and clinical studies suggest that bilirubin exhibits potent antioxidant, anti-inflammatory, anti-apoptotic, and cytoprotective properties that may protect the heart against oxidative stress, ischemia–reperfusion injury, and the progression of cardiovascular diseases, such as heart failure. As an endogenous hormone, bilirubin activates peroxisome proliferator-activated receptor-α (PPARα), a nuclear receptor that controls energy balance and lipid metabolism. Moderately elevated circulating bilirubin levels have been associated with a reduced risk of coronary artery disease, heart failure, and myocardial infarction; however, the mechanisms underlying bilirubin’s protective effects remain incompletely understood. Conversely, the gut microbiota’s metabolism of bilirubin to urobilin is detrimental, given urobilin’s association with cardiometabolic dysfunction. The therapeutic potential of bilirubin in the management of cardiovascular disease is becoming increasingly apparent, supported by preclinical research and emerging technologies that enhance bilirubin delivery via nanoparticles and methods to elevate plasma bilirubin levels. Collectively, these scientific advancements position bilirubin as a promising, biologically plausible endogenous therapeutic for the prevention and treatment of heart disease. Full article
(This article belongs to the Special Issue The Heme Oxygenase/Biliverdin Reductase System in Human Health and Disease: New Molecular Insights and Therapeutic Targets)
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19 pages, 743 KB  
Review
Preeclampsia Is a Double-Hit Vascular Disorder: The VEGF-HO-1-CSE Axis
by Asif Ahmed, Stephen K. Smith, Shakil Ahmad and Keqing Wang
Biomolecules 2026, 16(3), 436; https://doi.org/10.3390/biom16030436 - 13 Mar 2026
Viewed by 721
Abstract
Preeclampsia is a double-hit vascular disorder centred on the VEGF-HO-1-CSE axis. First, excess placental soluble Flt-1 (sFlt-1) neutralises vascular endothelial growth factor (VEGF) and placental growth factor (PlGF), producing an angiogenic deficit that drives endothelial dysfunction, hypertension, proteinuria and end organ injury. Second, [...] Read more.
Preeclampsia is a double-hit vascular disorder centred on the VEGF-HO-1-CSE axis. First, excess placental soluble Flt-1 (sFlt-1) neutralises vascular endothelial growth factor (VEGF) and placental growth factor (PlGF), producing an angiogenic deficit that drives endothelial dysfunction, hypertension, proteinuria and end organ injury. Second, the failure of endogenous vascular brakes, heme oxygenase-1 (HO-1/CO) and cystathionine-γ-lyase (CSE)/hydrogen sulfide (H2S) removes physiological restraint on anti-angiogenic factor release (sFlt-1; soluble endoglin) and amplifies oxidative–inflammatory stress, lowering the threshold at which VEGF loss precipitates severe disease. We synthesise human, animal and translational data that (i) establish placental sFlt-1 source and release, (ii) demonstrate human mechanistic causality via sFlt-1 removal, (iii) show prospective clinical validation that sFlt-1 rises and free PlGF falls before disease onset, and (iv) identify HO-1 and CSE/H2S as protective pathways that restrain anti-angiogenic drive. Finally, we summarise preclinical evidence that the orally administered H2S-donor prodrug MZe786 restores the HO-1/CSE axis, lowers sFlt-1 and soluble endoglin (sEng), and improves maternal haemodynamics and foetal outcomes across complementary pregnancy models, and we outline the role of sFlt-1/PlGF and M-PREG-based triage in clinical decision making. While valuable for short-term triage, current sFlt-1/PlGF-based approaches cannot sub-stratify among positive cases. Framing severe preeclampsia as a double-hit vascular disorder provides a biologically grounded framework that can inform risk stratification strategies like M-PREG®, a clinical decision support system informed by the double hit framework, and prevention strategies, pairing early risk stratification with mechanism-informed interventions. Full article
(This article belongs to the Special Issue The Heme Oxygenase/Biliverdin Reductase System in Human Health and Disease: New Molecular Insights and Therapeutic Targets)
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