Functional Characterization of the Hephaestin Variant D568H Provides Novel Mechanistic Insights on Iron‐Dependent Asbestos‐Induced Carcinogenesis

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.