In conclusion, we present a novel mitochondrial dysfunction-mediated retrograde signaling pathway, mitochondrial ROS-mediated STAT3 activation, and resulting transcriptomic reprogramming in liver cancer progression, providing the NDUFA9/NFE2L1/STX12 axis as a key prognostic marker of aggressive liver cancer with mitochondrial defect. The gene discussed is NFE2L1; the disease is liver cancer.