Our key findings indicate that (1): ERS upregulates CLGN expression, which is associated with enhanced HCC cell proliferation, migration, and anti-apoptotic activity (2); Elevated CLGN expression correlates with aggressive clinicopathological features and poor patient prognosis (3); The natural compound Paeonol (Pae) appears to counteract CLGN-mediated resistance, potentially by suppressing the CLGN/NF-κB axis, thereby restoring apoptosis sensitivity and inhibiting tumor growth in preclinical models. The gene discussed is NFKB1; the disease is hepatocellular carcinoma.