Local disruption of iron homeostasis leading to oxidative stress is considered one of the main mechanisms of asbestos-dependent cyto-/genotoxicity. Another aspect contributing to the risk of developing pathological consequences upon asbestos exposure is due to individual genetic fac-tors. In a previous study we identified a coding SNP in the hephaestin gene (HEPH) exerting a protective activity against the development of asbestos related thoracic cancers. Heph is a fer-roxidase which promotes iron export in concert with the permease ferroportin (Fpn1). Here, we performed an in-depth functional characterization of the HephD568H variant to gain insights on the molecular basis of its protective activity in asbestos-related carcinogenesis. We demonstrat-ed that HephD568H complexes with Fpn1 and possesses a full ferroxidase activity. Despite being more efficiently recruited at the plasma membrane, HephD568H is severely hampered in (iron-depleted) apo-Tfn binding, whose interaction with the WT ferroxidase emerged as a novel mechanism to perceive brain iron needs. Heph in human lung is expressed by pericytes and fi-broblasts and lung pericytes were shown to respond to iron request by up-regulating the iron exporter pair. These findings extend to the pulmonary vascular unit the paradigm of local iron regulation uncovered at the blood-brain barrier. Moreover, they mechanistically correlate alter-ations in iron sensing with the risk of developing asbestos-dependent malignancies.

A local disruption of iron homeostasis leading to oxidative stress is considered one of the main mechanisms of asbestos-related genotoxicity. Another aspect contributing to the risk of developing pathological consequences upon asbestos exposure is individual genetic factors. In a previous study, we identified a coding SNP in the hephaestin gene (HEPH) that protects against developing asbestos-related thoracic cancer. Heph is a ferroxidase that promotes iron export in concert with the permease ferroportin (Fpn1). Here, we performed an in-depth functional characterization of the HephD568H variant to gain insights into the molecular basis of its protective activity. We showed that HephD568H forms a complex with Fpn1 and possesses full ferroxidase activity. Although HephD568H is more efficiently recruited to the plasma membrane, it is impaired in binding iron-deficient Tfn, whose interaction with wild-type (WT) ferroxidase emerged as a novel mechanism to perceive brain iron needs. Heph is expressed in the human lung by pericytes and fibroblasts, and lung pericytes were shown to respond to iron demand by upregulating the iron exporter pair. These results extend the paradigm of local iron regulation discovered at the blood–brain barrier to the pulmonary vasculature. Furthermore, they establish a mechanistic link between changes in iron sensing and the risk of developing asbestos-related malignancies.