Although previous studies have already unveiled the high expression of ATF4 and its role in CAVD, differently, in the present study we verified the up-regulated ATF4 in CAVD through independent bioinformatics methods, demonstrated that knockdown of ATF4 could delay AVC in HC-induced mice, and confirmed that OxPL-polarized macrophages promoted osteogenic differentiation in CAVD by up-regulating ATF4 through PERK/eIF2α axis. The gene discussed is EIF2AK3; the disease is congenital bilateral aplasia of vas deferens from CFTR mutation.