BPHL (biphenyl hydrolase-like) encodes a serine hydrolase that serves multiple physiological functions. Its primary role is as an amino acid ester hydrolase with preference for small, hydrophobic, and aromatic side chains 1. BPHL catalyzes the hydrolytic activation of amino acid ester prodrugs of nucleoside analogs, converting valacyclovir to acyclovir and valganciclovir to ganciclovir, making it clinically significant for antiviral drug metabolism 12. The enzyme demonstrates broad substrate specificity for various therapeutic nucleoside analogues including acyclovir, zidovudine, floxuridine, and gemcitabine prodrugs 1. Additionally, BPHL functions as a highly efficient homocysteine thiolactonase with catalytic efficiency orders of magnitude higher than other known enzymes like PON1 or BLMH, potentially playing a significant role in detoxifying homocysteine thiolactone in cardiovascular disease prevention 3. However, studies in BPHL knockout mice demonstrate that other enzymes can compensate for valacyclovir activation, indicating BPHL is not obligatory for this process 4. Recent research suggests BPHL may also play roles in cancer biology, potentially promoting tumor growth in lung cancer and triple-negative breast cancer through various molecular mechanisms 56.