This study investigates the origin, evolution, and structural characteristics of lineage-specific de novo genes in *Drosophila melanogaster*. By combining high-quality whole-genome alignments and computational structural modeling, the authors identify 555 de novo gene candidates that originated within the *Drosophilinae* lineage. These genes exhibit gradual shifts in sequence composition, evolutionary rates, and expression patterns with their ages, suggesting adaptive or functional shifts. Surprisingly, few overall protein structural changes are observed in these genes. The study identifies several candidates with potentially well-folded protein structures, and ancestral sequence reconstruction analysis reveals that most well-folded candidates are well-folded in their ancestral stages. Single-cell RNA-seq data in the testis show that while most de novo gene candidates are enriched in spermatocytes, some young candidates are biased towards early spermatogenesis, indicating the importance of early germline cells in de novo gene origination. The findings provide a systematic overview of the foldability and structural evolution of *Drosophilinae*-specific de novo genes, highlighting the potential for de novo proteins to be well-folded and even adopt novel structural folds.This study investigates the origin, evolution, and structural characteristics of lineage-specific de novo genes in *Drosophila melanogaster*. By combining high-quality whole-genome alignments and computational structural modeling, the authors identify 555 de novo gene candidates that originated within the *Drosophilinae* lineage. These genes exhibit gradual shifts in sequence composition, evolutionary rates, and expression patterns with their ages, suggesting adaptive or functional shifts. Surprisingly, few overall protein structural changes are observed in these genes. The study identifies several candidates with potentially well-folded protein structures, and ancestral sequence reconstruction analysis reveals that most well-folded candidates are well-folded in their ancestral stages. Single-cell RNA-seq data in the testis show that while most de novo gene candidates are enriched in spermatocytes, some young candidates are biased towards early spermatogenesis, indicating the importance of early germline cells in de novo gene origination. The findings provide a systematic overview of the foldability and structural evolution of *Drosophilinae*-specific de novo genes, highlighting the potential for de novo proteins to be well-folded and even adopt novel structural folds.