HCAR1 (Hydroxycarboxylic Acid Receptor 1)

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.

It exerted its effects by regulating the GPX4/SLC7A11 axis to inhibit lipid peroxidation and malondialdehyde accumulation, thereby obstructing ferroptosis. Experimental validation demonstrated that the downregulation of HCAR1 promoted ferroptosis and suppressed malignant tumor phenotypes, suggesting that both the gene and its associated risk model hold significant clinical value as potential therapeutic targets and prognostic biomarkers.

Here, we report four cryo-EM structures of human HCAR1 and HCAR2 in complex with the Gi1 protein, in which HCAR1 binds to the subtype-specific agonist CHBA (3.16 Å) and apo form (3.36 Å), and HCAR2 binds to the subtype-specific agonists MK-1903 (2.68 Å) and SCH900271 (3.06 Å)...On this basis, we further summarize the structural features of agonists that match the orthosteric pockets of HCAR1 and HCAR2. These structural insights are anticipated to greatly accelerate the development of novel HCAR1-targeted drugs, offering a promising avenue for the treatment of various diseases.

They also emphasize the differences in C6 glioma cells regarding energetic metabolism. The proposed mechanism via HCAR1 provides further compelling evidence of the relationship between S100B and glucose metabolism.

NL01 exhibits better anti-tumor growth properties than curcumin, and NL01 induces ferroptosis in ovarian cancer cells.

Thus, there is an urgent need to fully identify the role of whole-grain-derived 3,5-DHBA during anticancer therapy and its contribution in the regulation of vital organs of the body via its specific HCAR1 receptor. We discuss here in detail the possible consequences of the modulatory capabilities of 3,5-DHBA in physiological and pathological conditions in humans.

Lactate monitoring is a simple, cost-efficient test that can offer point-of-care results. Our data suggest that the potential of circulating lactate as a screening biomarker in OvCa merits further research attention.