HCC, characterized by its immune‐suppressive milieu and chronic viral infections, employs unique protumorigenic mechanisms distinct from other tumors.[37, 38, 39, 40, 41] Particularly, when receive sorafenib, the cornerstone systemic therapy in the first‐line treatment, HCC patients develop resistance more rapidly than other tumors, underscoring the necessity of identifying liver cancer‐specific resistance mechanisms.[12, 15, 16, 17] Our investigation identified TRIB3 as a crucial determinant of sorafenib resistance. This evidence concerns the gene TRIB3 and liver cancer.