Extensively, in the present study, we proved that the elevated phosphor‐AMPK levels and the subsequent up‐regulated ATP levels were abrogated by SESN2 knockdown in HCC cells, implying that SESN2, as the critical upstream regulator was able to activate AMPK and promote ATP production, implicated in maintaining tumor cell survival. Here, SESN2 is linked to hepatocellular carcinoma.