Butyrate dictates ferroptosis sensitivity through FFAR2-mTOR signaling

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.

Automated summary

This study found that sodium butyrate (NaB) enhances RSL3- and erastin-induced cell ferroptosis by downregulating the expression of SLC7A11 and GPX4, leading to lipid ROS production. The FFAR2-AKT-NRF2 and FFAR2-mTORC1 axes mediate the downregulation of SLC7A11 and GPX4 by NaB in a cAMP-PKA-dependent manner. Functionally, NaB inhibits tumor growth and this effect can be reversed by the mTORC1 activator MHY1485 and the ferroptosis inhibitor Ferr-1. Overall, NaB treatment can induce mTOR-dependent ferroptosis and suppress tumor growth, suggesting its potential clinical applications for colorectal cancer treatment.