Hemichannels as an antibody therapeutic target. (A) Antibodies, either through the promotion of physiological or blocking of pathological hemichannel opening, are thought to be a unique approach to combat an array of diseases. (B) As an example, in osteocytes, the most abundant cells in bone, which express high levels of Cx43, forming both hemichannels (allowing communication between the intracellular and extracellular environments) and gap junctions (enabling direct cell-to-cell communication between adjacent osteocytes), antibodies present a unique approach to target specific hemichannels without affecting gap junctions. Immunoglobulin G (IgG) molecules, with a large molecular weight (~150 kDa) cannot access epitopes located within the tightly packed arrays of gap junctional plaques, where the intercellular space is limited (channel distance ~ 100 Å), Connexin hemichannels have two extracellular loops (E1 and E2) exposed to the extracellular environment, making them ideal targets for developing targeting antibodies. Among these loops, E2 has been shown to have the highest immune specificity [56]. Preclinical models have demonstrated the ability to utilize Cx43 hemichannel-blocking and activating antibodies targeting E2 in various disease states [19,25,57], and clinical trials are currently underway utilizing this approach in different clinical applications [36,37]. Created in BioRender. Acosta, F. (2024) BioRender.com/c15p060