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Blocking pyruvate carboxylase expression triggers ferroptosis and inhibits non-small cell lung cancer progression
Zhengping Che1, Cheng Zeng2, Dequan Jiang3
1School of Life Sciences, Chongqing University, Chongqing, 401331, China; Science and Technology Research Center, Harbin Medical University Cancer Hospital, Harbin, 150080, China.
Abstract:
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.
Insights
Pyruvate carboxylase (PC) drives non-small cell lung cancer (NSCLC) growth and ferroptosis resistance. Targeting PC or its regulators offers a new therapeutic strategy for NSCLC, enhancing ferroptosis and improving treatment outcomes.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Non-small cell lung cancer (NSCLC) presents a major global health burden with limited conventional therapy efficacy.
- Ferroptosis, a regulated cell death pathway, is a critical vulnerability in NSCLC, yet its regulatory mechanisms remain unclear.
- Identifying molecular drivers of ferroptosis sensitivity is crucial for developing novel NSCLC treatments.
Purpose of the Study:
- To identify key molecular regulators of ferroptosis in NSCLC.
- To elucidate the role of pyruvate carboxylase (PC) in NSCLC progression and ferroptosis resistance.
- To explore PC as a potential therapeutic target for NSCLC.
Main Methods:
- Analysis of PC expression in NSCLC tissues and correlation with clinical outcomes.
- In vitro and in vivo functional assays to assess PC's role in cell proliferation, migration, and invasion.
- Mechanistic studies investigating PC's impact on AMPK, AKT-mTOR, FASN, MCAT, PPARα, and ACSL4 signaling pathways.
- Investigation of PC regulation by DTX1 and USP51.
- Evaluation of therapeutic strategies combining USP51 inhibition (DHM) and anti-PD-1 therapy.
Main Results:
- Pyruvate carboxylase (PC) is highly expressed in NSCLC and linked to poor prognosis.
- PC promotes NSCLC cell proliferation, migration, and invasion.
- PC confers ferroptosis resistance by inhibiting AMPK activation, thereby promoting AKT-mTOR signaling and altering key metabolic pathways.
- PC is regulated by DTX1 and USP51, influencing ferroptosis susceptibility.
- Combined DHM (USP51 inhibitor) and anti-PD-1 therapy increased antitumor efficacy and ferroptosis in vivo.
Conclusions:
- Pyruvate carboxylase (PC) is a critical regulator of ferroptosis and a driver of NSCLC progression.
- Targeting PC or its regulators (like USP51) can sensitize NSCLC to ferroptosis.
- Blocking PC represents a promising therapeutic strategy for NSCLC treatment, potentially in combination with immunotherapy.
