Qi Li, Suiqing Zhou, Liren Zhang, Kai Yu, Chunyao Fang, X Liu, Xiaofeng Tie, Ruizhi Zhang, Hao Peng, Feifan Yao, Yuhong Tang, Song Tian, Yang Hu, Dianyu Liu, Feiyu Jin, Xiangyu Hou, Shu Chen, Guandou Yuan, Wenli Xu, Chaowen Zheng, Lirong Zhang, Jiaxing Zhang, Yufeng Hu, Zhi‐Gang She, Jingjing Dai, Xu Cheng, Songqing He, X Wang
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.