HCAR1/MCT1 Regulates Tumor Ferroptosis through the Lactate-Mediated AMPK-SCD1 Activity and Its Therapeutic Implications

Youbo Zhao 1, Menghuan Li 1, Xuemei Yao 1, Yang Fei 1, Zhenghong Lin 1, Zhengguo Li 1, Kaiyong Cai 2, Yanli Zhao 3, Zhong Luo 4

Ferroptosis is an iron-dependent form of programmed cell death, distinct from apoptosis and necrosis, and is characterized by metabolically driven lipid peroxidation. As a mechanism of cell death, ferroptosis holds considerable promise for cancer therapy, particularly in malignancies that exhibit resistance to conventional treatments. Despite its therapeutic potential, the regulatory pathways that control ferroptosis remain incompletely understood, especially in the context of altered tumor metabolism.

In this study, we demonstrate that hepatocellular carcinoma (HCC) cells exposed to high lactate levels display increased resistance to ferroptotic cell death induced by classical inducers such as Ras-selective lethal small molecule 3 (RSL3) and Erastin. Mechanistically, we identify the monocarboxylate transporter 1 (MCT1) as a key mediator of lactate uptake in HCC cells. This lactate import supports elevated ATP production, which in turn suppresses the energy stress sensor AMP-activated protein kinase (AMPK). Inactivation of AMPK leads to the activation of sterol regulatory element-binding protein 1 (SREBP1), a transcription factor that upregulates stearoyl-CoA desaturase-1 (SCD1), an enzyme responsible for the synthesis of monounsaturated fatty acids (MUFAs). These MUFAs act as protective agents against lipid peroxidation, thereby conferring ferroptosis resistance.

Importantly, we show that disruption of lactate uptake—via pharmacologic inhibition of MCT1 or the hydroxycarboxylic acid receptor 1 (HCAR1)—reactivates AMPK signaling. This activation results in SCD1 suppression and a corresponding decrease in MUFA synthesis, rendering HCC cells more vulnerable to ferroptosis. This sensitization is further potentiated by the upregulation of acyl-CoA synthetase long-chain family member 4 (ACSL4), an enzyme that facilitates the incorporation of polyunsaturated fatty acids into phospholipids, enhancing susceptibility to lipid peroxidation and ferroptotic cell death.

Our in vitro and in vivo data collectively establish lactate as a crucial metabolic regulator of ferroptosis in liver cancer. These findings expand our understanding of how metabolic adaptations contribute to ferroptosis resistance and underscore 7ACC2 the therapeutic potential of targeting lactate metabolism. Inhibiting the lactate–MCT1–AMPK–SCD1 axis may represent a novel strategy to enhance ferroptosis-based therapies in HCC.