umulating evidence supports the association of somatic mutations with tumor occurrence and development. We aimed to identify somatic mutations with important implications in hepatocellular carcinoma (HCC) and explore their possible mechanisms. The gene mutation profiles of HCC patients were assessed

and the tumor mutation burden was calculated. Gene mutations closely associated with tumor mutation burden and patient overall survival were identified.

In vivo

and

in vitro

experiments were performed to verify the effects of putative genes on proliferation

invasion

drug resistance

and other malignant biological behaviors of tumor cells. Fourteen genes with a high mutation frequency were identified. The mutation status of 12 of these genes was closely related to the mutation burden. Among these 12 genes

LRP1B

mutation was closely associated with patient prognosis. Nine genes were associated with immune cell infiltration. The results of

in vivo

and

in vitro

experiments showed that the knockdown of

LRP1B

promotes tumor cell proliferation and migration and enhances the resistance of tumor cells to liposomal doxorubicin.

LRP1B

could directly bind to

NCSTN

and affect its protein expression level

thereby regulating the PI3K/AKT pathway. Our mutational analysis revealed complex and orchestrated liposomal alterations linked to doxorubicin resistance that may also render cancers less susceptible to immunotherapy and also provides new treatment alternatives.