Epigenetic insights into anti-tuberculosis drug-induced liver injury: A systematic review of DNA methylation as a potential biomarker.

Drug-induced liver injury (DILI) remains a major clinical challenge that may cause acute liver failure, chronic liver disease, and treatment discontinuation. DNA methylation, a key epigenetic mechanism regulating gene expression, has emerged as a potential biomarker of DILI susceptibility; however, clinical evidence is largely confined to anti-tuberculosis drug-induced liver injury (ATDILI). This systematic review evaluated associations between DNA methylation patterns and DILI risk, with emphasis on ATDILI. Searches of PubMed, Scopus, and Embase identified eight eligible case-control studies published between 2014 and 2024. ATDILI-associated hypermethylation was reported in N-acetyltransferase-2 (NAT2), cytochrome P450 family-2 subfamily E member-1 (CYP2E1), cytochrome P450 family-2 subfamily D member-6 (CYP2D6), cytochrome P450 family-1 subfamily A member-1 (CYP1A1), glutathione S-transferase pi-1 (GSTP1), hypoxia-inducible factor-1 alpha (HIF1α), and 5-aminolevulinate synthase-1 (ALAS1). Global hypomethylation of repetitive elements, including LINE-1, SINE, and ALU, was also associated with increased ATDILI risk. Genome-wide analyses identified potential markers in tetratricopeptide repeat, ankyrin repeat, and coiled-coil containing-1 (TANC1), solute carrier family-8 member A-2 (SLC8A2), proline-serine-threonine phosphatase-interacting protein-2 (PSTPIP2), and adenylate kinase-2 (AK2). These findings support DNA methylation as a potential biomarker of ATDILI susceptibility and personalized risk assessment. However, because all evidence derives from case-control studies, causal and temporal relationships remain uncertain. Prospective longitudinal studies, epigenome-wide analyses, multi-omics integration, mechanistic validation, and large-scale replication are needed to confirm these associations and establish their predictive and clinical utility.