Our studies in 2D revealed, for the first time in HBMEC, that exposure to iRBC-egress products induces barrier breakdown as a consequence of decreased protein expression of the tight junctional marker claudin-5, in agreement with the well-documented role of claudin-5 as a key regulator of blood–brain barrier breakdown in in vivo models of multiple sclerosis (Argaw et al, 2009; Paul et al, 2013), traumatic brain injury (Campbell et al, 2012) and depression (Sun et al, 2024). This evidence concerns the gene CLDN5 and depressive disorder.