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AKR1C3 is an enzyme belonging to the aldo-ketoreductase family, the members of which catalyze redox transformations involved in biosynthesis, intermediary metabolism, and detoxification. AKR1C3 plays an important role in tumor progression and metastasis, however, little is known about the function and the molecular mechanism underlying the role of AKR1C3 in hepatocellular carcinoma (HCC). In this study, we report that AKR1C3 is significantly upregulated in HCC and that increased AKR1C3 is associated with poor survival. AKR1C3 positively regulated HCC cell proliferation and metastasis in vitro and in vivo . AKR1C3 promoted tumor proliferation and metastasis by activating NF-κB signaling. Furthermore, AKR1C3 regulated NF-κB activity by modulating TRAF6 and inducing its autoubiquitination in HCC cells. Activation of NF-κB released proinflammatory factors that facilitated the phosphorylation of STAT3 and increased tumor cell proliferation and invasion. Gain- and loss-of-function experiments showed that AKR1C3 promoted tumor proliferation and invasion via the IL6/STAT3 pathway. STAT3 also directly bound the AKR1C3 promoter and increased transcription of AKR1C3, thereby establishing a positive regulatory feedback loop. Treatment with the AKR1C3 inhibitors indocin and medroxyprogesterone acetate inhibited tumor growth and invasion and promoted apoptosis in HCC cells. Collectively, these results indicate that a AKR1C3/NF-κB/STAT3 signaling loop results in HCC cell proliferation and metastasis and could be a promising therapeutic target in HCC. SIGNIFICANCE: These findings elucidate a novel AKR1C3-driven signaling loop that regulates proliferation and metastasis in HCC, providing potential prognostic and therapeutic targets in this disease.

A Positive Feedback Loop of AKR1C3-Mediated Activation of NF-κB and STAT3 Facilitates Proliferation and Metastasis in Hepatocellular Carcinoma