Pillar 1 - FTO (new thread), page-1111

I have found a really cool paper regarding a new disease indication. I'm in the process of unpacking it now, but there is an interesting concept within the paper that I wanted to show you (1).

Sepsis is a systemic inflammatory response syndrome cause by infection that afflicts 18 million people worldwide and is a common cause of death in ICU. Global market value is estimated around USD $5.9B by 2026, an increase from USD $3.2B in 2018 (2). Currently, there are no clinically approved FTO inhibitors for sepsis shock or inflammatory diseases in general.



They demonstrated that the FTO inhibitor entacapone (~24.5 fold greater IC50 value than Bisantrene) inhibited macrophage activation, reduced tissue damage, and improved survival in a mouse model of LPS-induced endotoxic shock. Basically, it helped a mouse with a certain type of septic shock.

While opening up another avenue for a pharmaceutical company to explore is great, there is also an interesting concept that I wanted to show everyone. At the start of the trial, the researchers measured the FTO expression of normal patients and septic patients (A). The table below shows that the expression of FTO was lower in septic patients than normal patients. However, when FTO KD or an FTO inhibitor was used in mouse models (which would have further decreased FTO), it showed that it protected mice from LPS-induced endotoxic shock, decreased the inflammatory response and improved survival (two B charts).



So, FTO expression is already low and further inhibition/knockdown of FTO improved the outcome for the mice. I think that this is a good example of demonstrating the complexity of the m6a mechanism. I think this data may also help some of us conceptualise why an FTO inhibitor may be useful in cancerous cells that aren't necessarily FTO overexpressing. Even in low FTO expression cells, FTO inhibition can alter gene output, which changes proteins, and then cellular function.

Clearly, much more evidence is needed before we can make strong conclusions about which cancer types are appropriate for an FTO inhibitor, and I think this paper supports that notion.

1 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8128997/pdf/fimmu-12-663295.pdf
2 https://www.globaldata.com/sepsis-septic-shock-market-worth-5-9-billion-2026/