<i>HCAR1</i> Modulates Ferroptosis in Gastric Cancer via Lactate-Mediated AMPK-SCD1 Signaling and Lipid Metabolism

Ferroptosis is a type of regulated cell death characterized by iron-dependent lipid peroxidation, which has been linked to tumor progression and therapeutic resistance. However, the contribution of lactate metabolism and its receptor, hydroxycarboxylic acid receptor 1 (HCAR1), in ferroptosis regulation in gastric cancer (GC) remains poorly understood. Focusing specifically on its effects on cell proliferation, ferroptosis regulation, and the disruption of lactate-mediated metabolic pathways, the study aimed to clarify the role of HCAR1 in GC progression. Bioinformatics analysis identified prognostic genes associated with ferroptosis in GC. Receiver operating characteristic (ROC) curves were generated to assess the diagnostic potential of the predictive genes. The biological role of HCAR1 was investigated through gain and loss-of-function experiments in GC cell lines, followed by assessments of cell viability, oxidative stress indicators, gene/protein expression, and ferroptosis sensitivity under lactate stimulation or HCAR1 modulation. HCAR1 was significantly upregulated in GC tissues and linked to poor patient outcomes. Silencing HCAR1 inhibited GC cell growth and induced ferroptosis, as shown by increased levels of reactive oxygen species (ROS) and malondialdehyde (MDA), along with decreased expression of solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4). Conversely, HCAR1 overexpression or exposure to extracellular lactate inhibited ferroptosis and activated antioxidant defenses. Mechanistically, lactate activation of HCAR1 increases ATP levels, which in turn inactivates AMP-activated protein kinase (AMPK). It also upregulates stearoyl-CoA desaturase 1 (SCD1) through the sterol regulatory element binding protein 1 (SREBP1) signaling pathway. Blocking HCAR1 reversed these effects and restored ferroptosis sensitivity. HCAR1 mediates lactate-driven ferroptosis resistance in GC through the AMPK-SCD1 signaling pathway. Targeting the HCAR1-lactate axis may offer a promising strategy for overcoming metabolic adaptation and improving GC treatment outcomes.