Human Leukocyte Antigen (HLA) Signatures and Idiosyncratic Drug-Induced Liver Injury

Drug-induced liver injury (DILI) remains one of the most challenging adverse drug reactions in clinical practice, particularly in its idiosyncratic form, which is not dose-dependent and is largely driven by host-specific immune and genetic factors. Recent genomic studies have revealed strong associations between certain human leukocyte antigen (<i>HLA</i>) alleles and susceptibility to DILI, supporting an immunogenetic mechanism in which drug or metabolite-protein adducts act as neoantigens, triggering aberrant T-cell activation and hepatocellular injury. This review summarizes current evidence on the contribution of <i>HLA</i> polymorphisms to the pathogenesis of idiosyncratic DILI, highlighting allele-specific risk patterns, such as <i>HLA</i>-<i>B*57:01</i> associated with flucloxacillin, <i>HLA</i>-<i>DRB1*15:01-DQB1*06:02</i> in amoxicillin-clavulanate, and <i>HLA-B*35:02</i> in minocycline-induced liver injury. Furthermore, ethnic variability and allele-haplotype interactions are discussed as potential modulators of susceptibility and clinical phenotype. By integrating genetic and immunological insights, the identification of <i>HLA</i> signatures offers promising tools for precision medicine, enabling earlier identification of at-risk individuals and improved prevention of severe hepatotoxic reactions.