ReviewFrontiers in pharmacology2026
The HO-1/bilirubin axis in cardiovascular protection: critical evidence for modulation by plant metabolites and traditional multi-component formulations used in Chinese medicine.
Review in Frontiers in pharmacology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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9 authors.
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Abstract
Bilirubin was long regarded primarily as a waste product of haem catabolism, but accumulating experimental and epidemiological evidence suggests that, within an appropriate concentration range, it may contribute to cardiovascular protection through antioxidant, anti-inflammatory, endothelial, metabolic, and mitochondrial effects. Haem oxygenase-1 (HO-1) is a key inducible enzyme in bilirubin formation because it converts haem to biliverdin, which is subsequently reduced to bilirubin. However, HO-1 activation also produces carbon monoxide and ferrous iron, and increased HO-1 expression alone does not demonstrate enhanced bilirubin production or bilirubin-mediated protection. This critical narrative review first examines the biological basis and evidential limits of bilirubin-related cardiovascular protection and then evaluates whether selected plant metabolites and traditional multi-component formulations used in Chinese medicine engage the HO-1/bilirubin axis in cardiovascular models. Curcumin provides the most direct evidence of pathway engagement because HO activity, circulating bilirubin, pharmacological inhibition, and HO-1 silencing were assessed. Dihydromyricetin shows HO-1-dependent vascular protection, although bilirubin was not measured. For most other metabolites and formulations, the evidence is limited to Nrf2/HO-1-associated signalling in preclinical models. Material characterisation, dose justification, bioavailability, pharmacokinetics, safety assessment, and direct measurement of haem-catabolic products remain inconsistent. The available data support the HO-1/bilirubin axis as a biologically plausible link between selected interventions used in Chinese medicine and cardiovascular protection, but direct bilirubin-specific causality remains unproven. Future studies should combine standardised materials, exposure-confirmed dosing, direct quantification of bilirubin and biliverdin,
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