SMPDL3B a novel biomarker and therapeutic target in myalgic encephalomyelitis, July 2025

[bad1080]

Abstract​

Background​

Sphingomyelin phosphodiesterase acid-like 3B (SMPDL3B) is emerging as a potential biomarker and therapeutic target in myalgic encephalomyelitis (ME), a complex multisystem disorder characterized by immune dysfunction, metabolic disturbances, and persistent fatigue. This study investigates the role of SMPDL3B in ME pathophysiology and explores its clinical relevance.

Methods​

A case–control study was conducted in two independent cohorts: a Canadian cohort (249 ME patients, 63 controls) and a Norwegian replication cohort (141 ME patients). Plasma and membrane-bound SMPDL3B levels were quantified using ELISA and flow cytometry. Gene expression of SMPDL3B and PLCXD1, encoding phosphatidylinositol-specific phospholipase C (PI-PLC), was analyzed by qPCR. The effects of dipeptidyl peptidase-4 (DPP-4) inhibitors—vildagliptin, saxagliptin, and linagliptin—on modulation of membrane-bound and soluble SMPDL3B were assessed in vitro by qPCR, flow cytometry and ELISA.

Results​

ME patients exhibited significantly elevated plasma SMPDL3B levels, which correlated with symptom severity. Flow cytometry revealed a reduction in membrane-bound SMPDL3B in monocytes, accompanied by increased PLCXD1 expression and elevated plasma levels of PI-PLC and SMPDL3B. These findings suggest that immune dysregulation in ME may be linked to enhanced cleavage of membrane-bound SMPDL3B by PI-PLC. Sex-specific differences were observed, with female ME patients displaying higher plasma SMPDL3B levels, an effect influenced by estrogen. In vitro, estradiol upregulated SMPDL3B expression, indicating hormonal regulation. Vildagliptin and saxagliptin were tested for their potential to inhibit PI-PLC activity independently of their role as DPP-4 inhibitors, and restored membrane-bound SMPDL3B while reduced its soluble form.

Conclusions​

SMPDL3B emerges as a key biomarker for ME severity and immune dysregulation, with its activity influenced by hormonal and PI-PLC regulation. The ability of vildagliptin and saxagliptin to preserve membrane-bound SMPDL3B and reduce its soluble form via PI-PLC inhibition suggests a novel therapeutic strategy. These findings warrant clinical trials to evaluate their potential in mitigating immune dysfunction and symptom burden in ME.

https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-025-06829-0

 

[bad1080]

Vildagliptin:
https://en.wikipedia.org/wiki/Vildagliptin
https://www.drugs.com/uk/galvus.html

Saxagliptin:
https://en.wikipedia.org/wiki/Saxagliptin
https://www.drugs.com/mtm/saxagliptin.html

(curiously both diabetes medication)

 

[Wishful]

Are those drugs rarely prescribed? If they're common, the lack of PWME saying "These reduce my symptoms!" suggests it's probably a false hypothesis.

 

[bad1080]

Are those drugs rarely prescribed? If they're common, the lack of PWME saying "These reduce my symptoms!" suggests it's probably a false hypothesis.

from drugs.com:

In the study comparing Galvus with metformin, significantly better results were seen with metformin

i guess they prescribe metformin over Vildagliptin and judging from the length of the wikipedia article it's not very common but that's speculation on my part

they both got approved around the same time (2007 and 2009) but metformin is considerably older:

It was introduced as a medication in France in 1957.[15] Metformin became available in the British National Formulary in 1958.

https://en.wikipedia.org/wiki/Metformin#History

this might be a reason they are cautious about prescribing Saxagliptin:

In April 2016, the U.S. FDA added a warning about increased risk of heart failure.[3]

https://en.wikipedia.org/wiki/Saxagliptin

edit:
r/cfs (60k subscribers) returns zero results for all three terms (Vildagliptin, galvus and Saxagliptin)
r/diabetes (145k subscribers) returns 15 results for "Vildagliptin", 8 for "galvus" and 5 results for "Saxagliptin" while "metformin" returns roughly 250 results (10 pages with 25 results per page)

 

[cfs since 1998]

The doses of Vildagliptin and Saxagliptin would need to be very high in order to reach the required concentrations (100 microMolar) that were effective in the study.

 

[bad1080]

The doses of Vildagliptin and Saxagliptin would need to be very high in order to reach the required concentrations (100 microMolar) that were effective in the study.

do you have any idea how large a dose would have to be to achieve that kind of concentration? or differently what kind of concentration the regular dose achieves (i've seen 50mg vildagliptin pills)?

 

[Alvin2]

Saw this in an OMF email, not sure what to try on it.

 

[NameHere]

https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-025-06829-0

ME patients exhibited significantly elevated plasma SMPDL3B levels

I am not seeing many ME participants who have elevated levels of SMPDL3B in this study....

I am reading this study. It may take me a few days to finish reading it. However, immediately, I noticed in figure 2a that it appears that the healthy controls all have levels between 0 to 100 ng/mL, and that the vast majority of the ME participants are also in that range, with only just a few who are not.

So, it appears to me that there are just a few people who have their SMPDL3B fall outside of this range.

Am I missing something?

I see that the study is trying to claim that there is some special significance to the level of 30ng/mL, but I just don't see that here. There are many healthy controls (looks like 16 out of 63, or 25% in fact) who are above that level. To me, it looks like 0 to 100 ng/mL is established as a healthy level.

 

[bad1080]

I am not seeing many ME participants who have elevated levels of SMPDL3B in this study....

if you look at the p values:

Differences were found to be significant at *P < 0.05, **P < 0.01, *** P-value < 0.001 and ****P < 0.0001

you can glean how confident they are with their findings, the lower the p value the less likely they made a mistake.