Recent Insights into HLA-dependent Idiosyncratic Liver Injury

Idiosyncratic drug-induced liver injury (iDILI) is a rare but serious adverse reaction that occurs only in a small subset of individuals. Traditionally, drug-induced liver injury has been studied primarily through the lens of hepatocellular toxicity; however, this approach fails to explain the unpredictable nature of iDILI, which often evades detection in preclinical models. Recent studies have shifted the paradigm toward an immune-mediated mechanism, with CD8⁺ T cell activation restricted by specific human leukocyte antigen (HLA) class I alleles playing a central role. Nevertheless, the presence of a risk HLA allele alone is insufficient to induce disease, underscoring the importance of additional host-specific factors that regulate immune responsiveness. Among these, breakdowns in immune tolerance-such as impaired regulatory T cell function or immune checkpoint failure-appear critical in unleashing pathological T cell activity. Importantly, effective CD8⁺ T cell activation also requires more than antigen recognition. While HLA-mediated antigen presentation (signal 1) provides specificity, co-stimulatory signals (signal 2) from activated antigen-presenting cells are necessary to drive full activation. The convergence of these two signals, in the context of a permissive immune environment, initiates tissue-damaging immune responses. This stepwise framework offers a more accurate understanding of iDILI as an immunologically orchestrated process rather than a purely toxicological phenomenon. Although HLA-transgenic mouse models seldom reproduce overt liver injury, they serve as valuable platforms for investigating HLA-restricted immune responses in vivo and lay the foundation for improved risk prediction, mechanistic modeling, and safer therapeutic strategies.