Blocking pyruvate carboxylase expression triggers ferroptosis and inhibits non-small cell lung cancer progression.

Non-small cell lung cancer (NSCLC) continues to pose a significant global health challenge, as conventional therapies often exhibit limited effectiveness. Ferroptosis has emerged as a critical vulnerability across diverse malignancies, including NSCLC, offering a promising opportunity for therapeutic intervention. Nevertheless, molecular mediators dictating ferroptosis sensitivity and exploitable vulnerabilities remain largely elusive in NSCLC. In this study, pyruvate carboxylase (PC) is identified as a pivotal ferroptosis regulator that is highly expressed in NSCLC tissues and associated with aggressive progression and poor prognosis. Functionally, PC promotes NSCLC cell proliferation, migration, and invasion both in vitro and in vivo. Mechanistically, PC confers resistance to ferroptosis by suppressing AMPK activation in an ATP-dependent manner, thereby activating the AKT-mTOR signaling pathway, upregulating fatty acid synthase (FASN) and malonyl-CoA-acyl carrier protein transacylase (MCAT), and ultimately inhibiting the PPARα-ACSL4 axis. Further analyses revealed that PC is targeted by Deltex E3 ubiquitin ligase 1 (DTX1) and ubiquitin-specific peptidase 51 (USP51), which modulate NSCLC progression by altering ferroptosis susceptibility. Therapeutically, the combination of the USP51 inhibitor dihydromyricetin (DHM) and anti-PD-1 treatment enhances antitumor efficacy with increased ferroptosis in vivo. Collectively, these results demonstrate that blocking PC facilitates ferroptosis, highlighting PC as a potential therapeutic target for NSCLC.