KEGG enrichment analysis re-vealed that the differentially expressed genes (DEGs) between high and low Cd accumulation in-dividuals, as well as those before and after Cd exposure, were primarily enriched in metabolic pathways (33.8%) and organismal systems (32.2%). ABC transporters, phagosome, glutathione metabolism, and biosynthesis of amino acids played crucial roles in Cd accumulation and detoxi-fication processes. Metal cation transport-related genes, including zip1, copt5.1, and orct2, may be involved in the Cd transport process in Portuguese oysters, and their differential expression influ-ences Cd accumulation in the soft tissues. Meanwhile, genes such as sod3, cyp4f22, and abca3 are likely to play significant roles in detoxification under Cd exposure. Additionally, alternative splicing analysis identified 13 potential genes associated with Cd response in Portuguese oysters, including cs2, gfpt1, acox1.