While HERC5 has thus far been described mainly in the context of ISGylation and innate immune responses [11, 12], here, we show, for the first time, that HERC5 also directly promotes carcinogenicity and metastasis in NSCLC mainly through a switch in energy metabolism, which is independent of its ISGylation function. Here, HERC5 is linked to non-small cell lung carcinoma.