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The transition from traditional mulberry leaf feeding to artificial diet cultivation represents a major advancement in modern sericulture, yet the genetic mechanisms driving this adaptation remain largely unexplored. This study investigates the genomic basis of artificial diet adaptation in the silkworm strain Guican No.5 through whole-genome resequencing and transcriptome analysis. We identified 8,935,179 single-nucleotide polymorphisms (SNPs) across all chromosomes, accounting for 2.01% of the genome, with particularly high densities observed in chromosomes 23, 26, and 28. Our analysis also revealed 879 novel transcripts, many of which are involved in digestion, detoxification, and stress response pathways. Key novel genes, including three carboxylesterases, two cytochrome P450s, one heat shock protein, and one copper/zinc superoxide dismutase, exhibited varying degrees of sequence similarity to known proteins, suggesting modifications to existing genetic frameworks. Notably, one novel P450 gene displayed only 74.07% sequence identity with its closest homolog, indicating the emergence of a new protein sequence. Additionally, several key genes showed high similarity to wild silkworm (Bombyx mandarina) proteins, underscoring their evolutionary origins. These findings provide valuable insights into the molecular mechanisms underpinning artificial diet adaptation in silkworms and offer genomic resources to enhance artificial diet formulations and breeding programs in sericulture. Full article