Histone lysine lactylation has emerged as a key epigenetic link between metabolism and gene regulation. Its homeostasis depends on both lactylation and delactylation. The biological and clinical relevance of histone lysine delactylation in hepatocellular carcinoma (HCC) remains unclear. This study aimed to investigate the clinical relevance of histone lysine delactylation (HLDL) in hepatocellular carcinoma and to establish an HLDL-based molecular classification for precision therapy.

We systematically profiled HLDL across multi-omics HCC cohorts (n > 1700) to establish an HLDL-based molecular classification. Distinct subtypes were characterized by genomic, transcriptomic, and immune features. Therapeutic susceptibilities were predicted through pharmacogenomic modeling and validated by in vitro modulation of histone lysine lactylation.

The HLDL classification delineated two major subtypes with distinct biological and therapeutic profiles. Low-HLDL tumors displayed higher genomic instability, activated oncogenic signaling, and an immuneinfiltrated yet suppressive microenvironment, corresponding to poorer outcomes but higher sensitivity to immune checkpoint inhibitors, atezolizumab plus bevacizumab therapy, and sorafenib. In contrast, high-HLDL tumors exhibited a metabolically stable and delactylation-active phenotype, responding more favorably to lenvatinib and transarterial chemoembolization. Functional experiments confirmed that reduced HLDL activity led to elevated histone lysine lactylation, PD-L1 upregulation, and lenvatinib resistance, whereas restoring delactylation reversed these effects.

Histone lysine delactylation constitutes a critical epigenetic determinant of HCC heterogeneity and therapeutic response. The HLDL-based classification developed in this study integrates metabolic, immune, and pharmacologic features into a concise framework, offering new avenues for precision therapy and potential targets for modulating the lactylation-delactylation balance in HCC.