Polyploidy represents a major driver of eukaryotic genome evolution. In vertebrates, premeiotic endoreplication is considered as an important route to polyploidization, yet the molecular basis governing this process remains elusive. Here, we reported that heterozygous mutation of cdk1 in the loach, Misgurnus anguillicaudatus (Teleostei, Cobitidae), triggered premeiotic endoreplication in spermatogonia, resulting in the production of unreduced diploid sperms. Through integrated proteomic and phosphoproteomic profiling, we uncovered that Cdk1 heterozygosity led to widespread dysregulation of the phosphorylation of key proteins in the cell cycle and DNA replication pathways in spermatogonia. Mechanistically, Cdk1 heterozygosity induced increased inhibitory phosphorylation of Cdk2 at tyrosine 15, and accumulated Cdk2/Ccne1 complex directly phosphorylated Fzr1a at threonine 124, inhibiting APC/C ^Fzr1a complex activity. Cdk2 Y15 phosphorylation arrested cells at the G1/S boundary, while Fzr1a phosphorylation-driven APC/C ^Fzr1a inactivation blocked mitotic exit and sustained DNA replication, thereby triggering premeiotic endoreplication. Inhibition of Cdk2 expression in cdk1 ^+/− loach males suppressed this pathway and abolished unreduced sperm formation. Our study elucidates the molecular pathway for unreduced gamete production in fish and establishes Cdk1 as a key guardian of diploidy before meiosis. Furthermore, leveraging this mechanism, we generated triploid and tetraploid loach lines with unreduced sperms, demonstrating a direct bridge between gene function and polyploid breeding. These findings provide a mechanistic framework for understanding polyploidization in vertebrate evolution and offer a targeted strategy for chromosome set manipulation in aquaculture.

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