AKR1B1, a rate-limiting enzyme in the polyol pathway, catalyzes the reduction of glucose to sorbitol and consequently modulates cellular metabolism and energy homeostasis.24,25 Previous studies have demonstrated that, in lung cancer cells, AKR1B1 can interact with STAT3 to regulate the expression of the cystine transporter SLC7A11, thereby promoting resistance to TKIs.26 For the first time, our study revealed that AKR1B1 is critically involved in mediating resistance in HCC by modulating metabolic reprogramming. This evidence concerns the gene STAT3 and lung carcinoma.