The HO-1/bilirubin axis in cardiovascular protection: critical evidence for modulation by plant metabolites and traditional multi-component formulations used in Chinese medicine

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, HMOX1/BVRA manipulation, and product-specific rescue experiments.