Butyrate dictates ferroptosis sensitivity through FFAR2-mTOR signaling

by Selleckchem | Jun 30 2023

Evidence shows that short-chain fatty acids (SCFAs) play an important role in health maintenance and disease development. In particular, butyrate is known to induce apoptosis and autophagy. However, it remains largely unclear whether butyrate can regulate cell ferroptosis, and the mechanism by which has not been studied. In this study, we found that RAS-selective lethal compound 3 (RSL3)- and erastin-induced cell ferroptosis were enhanced by sodium butyrate (NaB). With regard to the underlying mechanism, our results showed that NaB promoted ferroptosis by inducing lipid ROS production via downregulating the expression of solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4). Moreover, the FFAR2-AKT-NRF2 axis and FFAR2-mTORC1 axis accounts for the NaB-mediated downregulation of SLC7A11 and GPX4, respectively, in a cAMP-PKA-dependent manner. Functionally, we found that NaB can inhibit tumor growth and the inhibitory effect could be eliminated by administrating MHY1485 (mTORC1 activator) and Ferr-1 (ferroptosis inhibitor). Altogether, in vivo results suggest that NaB treatment is correlated to the mTOR-dependent ferroptosis and consequent tumor growth through xenografts and colitis-associated colorectal tumorigenesis, implicating the potential clinical applications of NaB for future colorectal cancer treatments. Based on all these findings, we have proposed a regulatory mechanism via which butyrate inhibits the mTOR pathway to control ferroptosis and consequent tumorigenesis.

Comments:

Your study suggests that sodium butyrate (NaB) enhances cell ferroptosis induced by RAS-selective lethal compound 3 (RSL3) and erastin. Ferroptosis is a form of regulated cell death characterized by the accumulation of lipid reactive oxygen species (ROS). The underlying mechanism involves the downregulation of solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4) by NaB, leading to increased lipid ROS production.

The study further reveals two axes through which NaB exerts its effects. The FFAR2-AKT-NRF2 axis is responsible for the downregulation of SLC7A11, while the FFAR2-mTORC1 axis is involved in the downregulation of GPX4. These axes are activated in a cAMP-PKA-dependent manner. Activation of the FFAR2-AKT-NRF2 axis leads to decreased SLC7A11 expression, impairing cellular antioxidant capacity. Activation of the FFAR2-mTORC1 axis results in decreased GPX4 expression, compromising the cell's ability to inhibit lipid peroxidation.

The functional implications of these findings are highlighted by the inhibitory effect of NaB on tumor growth. NaB treatment leads to mTOR-dependent ferroptosis and subsequent suppression of tumor growth. This effect is demonstrated in xenografts and colitis-associated colorectal tumorigenesis models. The anti-tumor effect of NaB can be counteracted by administering an mTORC1 activator (MHY1485) or a ferroptosis inhibitor (Ferr-1).

Overall, the study proposes a regulatory mechanism by which butyrate inhibits the mTOR pathway to control ferroptosis and subsequent tumorigenesis. These findings provide insights into the potential clinical applications of NaB for colorectal cancer treatment.