Schistosoma japonicum histone acetyltransferase 1 (SjHAT1): A novel anti-schistosomal drug target

Schistosomiasis remains a critical global health issue, necessitating novel therapies due to emerging praziquantel resistance. We previously developed a patented praziquantel derivative, DW-3-15, which demonstrated potent broad-spectrum schistosomicidal activity through SjHAT1 inhibition. Here, the full-length SjHAT1 cDNA is cloned by rapid amplification of cDNA ends methods. The protein encoded by the cDNA retains conserved catalytic residues of acetyltransferases although sharing 34% identity with mammalian orthologs. Enzyme activity analysis reveals that recombinant SjHAT1 exhibits 130 μU/mL histone acetyltransferase activity at 25°C for 60 min, and is completely inhibited by DW-3-15 at a concentration of 50 μM. However, DW-3-15 has no effect on the enzymatic activity of the human ortholog HAT1. Phylogenetic analyses place SjHAT1 in a distinct clade, and molecular docking results indicate significant divergence compared to its human ortholog HsHAT1. The expression profiling of SjHAT1 reveals stage- and sex-specific patterns. Fluorescence in situ hybridization localizes SjHAT1 predominantly in female vitellaria and male parenchyma near the gynecophoral canal. Knockdown of SjHAT1 reduces worm survival by 57.5% in vivo, suppresses female oviposition by 90.8% in vitro and 79.2% in vivo, and disrupts ovarian and vitelline architecture. RNA-sequencing analysis reveals that SjHAT1 knockdown disrupts β-alanyl-tryptamine (BATT) pheromone signaling via downregulation of aromatic L-amino acid decarboxylase (AADC) in males and multidrug resistance-associated protein 4 (MRP4) in females. Given that BATT is essential for inducing female sexual development and egg production, the observed transcriptional dysregulation provides mechanistic evidence for disrupted intersexual communication. Our findings identify that SjHAT1 is a central regulator of schistosome reproductive biology. These sex-specific mechanisms highlight SjHAT1 as a potential therapeutic target for treatment and control of schistosomiasis.