NF-κB and STAT3 are key regulators of liver inflammation and cancer. NF-κB promotes hepatocyte survival and inflammatory responses by controlling cytokine expression, including IL-6, which activates STAT3. STAT3 is critical for liver regeneration and HCC development. Both pathways are involved in liver injury, inflammation, and cancer, with complex interactions. NF-κB suppresses HCC by maintaining antioxidant defenses and preventing excessive ROS accumulation, while STAT3 promotes HCC by maintaining inflammatory responses. In some models, NF-κB activation enhances HCC development, whereas in others, it suppresses it. STAT3 is also involved in tumor progression through its role in cell proliferation and survival. Therapeutic targeting of STAT3, such as with inhibitors like S3I-201 and AG490, shows promise in reducing HCC growth. The crosstalk between NF-κB and STAT3 is crucial for liver homeostasis and cancer development. Understanding these pathways offers potential therapeutic strategies for HCC.NF-κB and STAT3 are key regulators of liver inflammation and cancer. NF-κB promotes hepatocyte survival and inflammatory responses by controlling cytokine expression, including IL-6, which activates STAT3. STAT3 is critical for liver regeneration and HCC development. Both pathways are involved in liver injury, inflammation, and cancer, with complex interactions. NF-κB suppresses HCC by maintaining antioxidant defenses and preventing excessive ROS accumulation, while STAT3 promotes HCC by maintaining inflammatory responses. In some models, NF-κB activation enhances HCC development, whereas in others, it suppresses it. STAT3 is also involved in tumor progression through its role in cell proliferation and survival. Therapeutic targeting of STAT3, such as with inhibitors like S3I-201 and AG490, shows promise in reducing HCC growth. The crosstalk between NF-κB and STAT3 is crucial for liver homeostasis and cancer development. Understanding these pathways offers potential therapeutic strategies for HCC.