PDCL2 maintains redox homeostasis under physiological ROS to drive spermiogenesis

Abstract Reactive oxygen species (ROS) are a double-edged sword—licensing essential programs yet risking injury. Spermiogenesis is a redox-intense remodeling phase whose control remains obscure. By mining testis-enriched thioredoxin-like proteins, we identify phosducin-like protein 2 (PDCL2) as a non-redundant antioxidant essential for sperm morphogenesis. We delineate a physiological, stage-restricted ROS pulse in wild-type spermatids—coordinated rise-and-fall dynamics coincident with nuclear condensation and transient DNA breaks—whereas in Pdcl2 –/– cells ROS elevates prematurely and persists through spermiogenesis, yielding reduced sperm-head size and manchette/flagellar disarray. Mechanistically, excess ROS drives aberrant polymerization of structural proteins and disrupts cytoskeletal organization. PDCL2 binds UPP2, preserves its redox competence, and sustains nucleotide-pool balance to enable repair during the histone-to-protamine transition; PDCL2 loss causes UPP2 dysfunction, nucleotide imbalance, inefficient repair, DNA fragmentation, and post-fertilization arrest. These results define a PDCL2-centered redox axis that constrains ROS within a permissive window, reframing physiologically high ROS as a licensing signal for sperm-head shaping and establishing a generalizable framework for redox control in cellular remodeling and oxidative-stress disorders.