L-lactate-driven PSMD14 lactylation and stabilization promote lactate production and ferroptosis resistance via ENO1 in intrahepatic cholangiocarcinoma.

Targeting ferroptosis is a promising treatment strategy for intrahepatic cholangiocarcinoma (ICC) given the limited number of currently available therapeutic drugs. However, the heterogeneity of tumor cells and their resistance to ferroptosis pose difficulties in the implementation of this strategy. Here, we constructed a novel ferroptosis resistance score (FRS) to quantitatively assess the ferroptosis resistance status of ICC samples. Next, we found that glycolysis is closely associated with the FRS and verified that L-lactate drives ferroptosis resistance via PSMD14 in vitro and in vivo. Mechanistically, L-lactate promoted the K100 lactylation of PSMD14 to delay proteasome-mediated degradation. PSMD14 subsequently interacted with ENO1 to decrease ENO1 K63-linked ubiquitination and inhibited lysosome-mediated ENO1 degradation. Importantly, targeting PSMD14 inhibited L-lactate production and ferroptosis resistance through ENO1 and significantly increased the efficacy of anti-PD-1 treatment. Furthermore, PSMD14 and ENO1 were highly expressed in tumor tissues and closely associated with a poor ICC prognosis. Overall, our study reveals the importance of the L-lactate/PSMD14/ENO1 axis in regulating ferroptosis resistance in ICC, suggesting a novel therapeutic target and strategy for treating this disease.