Landscape screening identifies the lactate-modifying enzyme AARS2 as a master regulator and therapeutic target in hepatocellular carcinoma

Background Hepatocellular carcinoma (HCC), one of the most prevalent cancers worldwide, has a high mortality owing to diagnostic challenges and therapeutic resistance. Lactate metabolism and protein lactylation play key roles in HCC progression; nevertheless, their regulatory mechanisms remain poorly understood. Objective This study aims to elucidate how lactate metabolism and protein lactylation contribute to HCC malignant progression by integrating multi-omics data, identifying key regulatory factors and exploring therapeutic strategies targeting this pathway. Design Integrated multi-omics analysis identified AARS2–AP-2γ as a key axis in HCC. Through mechanistic studies and virtual screening, we developed kukoamine A—a targeted inhibitor delivered via nanocarriers—demonstrating significant therapeutic potential. Results AARS2 was identified as a key regulator linking lactate metabolism to HCC progression through lactylation modification. It catalyses AP-2γ lactylation at K444, enhancing TRIM28 binding to promote K63-linked ubiquitination and nuclear translocation, thereby facilitating tumour progression. The inhibitor kukoamine A disrupts AARS2–AP-2γ interaction and, when delivered via zeolitic imidazolate framework-8 nanocarriers, demonstrates improved liver targeting, potent antitumour activity and synergy with PD-1 blockade, offering new strategic avenues for HCC precision therapy. Conclusion AARS2 links lactate metabolism to HCC progression via lactylation. Kukoamine A nanotherapy targeting this axis shows synergistic efficacy with immunotherapy, advancing the prospects of precision oncology.