Maternal TCL1 enables early embryonic development partially through HSD17B4-dependent CDCA metabolism

Oocyte quality governs early embryonic development and female fertility. Here, we demonstrate that the maternal effect gene Tcl1 supports oocyte cytoplasmic competence through metabolic regulation. Although Tcl1 -deficient females maintain a normal follicle reserve and undergo proper meiotic progression, their embryos predominantly arrest after the 2-cell stage, resulting in reduced fertility. Quantitative proteomic and metabolomic analyses reveal a significant decrease in the abundance of the peroxisomal β-oxidation enzyme HSD17B4, accompanied by reduced chenodeoxycholic acid (CDCA) levels in Tcl1 -mutant oocytes. Notably, zygotic knockdown of Hsd17b4 partially recapitulated the developmental arrest after the 2-cell stage, whereas supplementation with either Hsd17b4 mRNA or exogenous CDCA partially rescued blastocyst formation in embryos derived from Tcl1 -deficient oocytes. Transcriptome profiling further indicates that Tcl1 deficiency impairs major zygotic genome activation (ZGA), a defect that is partially alleviated by CDCA. Together, our findings suggest that maternal TCL1 sustains HSD17B4-linked metabolism and maintains CDCA levels, thereby ensuring the metabolic competence required for successful major ZGA and early development. This mechanistic insight provides a rationale for exploring potential therapeutic strategies to improve embryonic developmental outcomes.