On the 7th July, a research paper entitled ‘SMPDL3B a novel biomarker and therapeutic target in myalgic encephalomyelitis‘ (Rostami-Afshari et al 2025) was published on Journal of Translational Medicine.
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.
MEA Comment
There are now several research groups around the world who are making use of blood based abnormalities to try and find a reliable diagnostic biomarker for ME/CFS.
Here in the UK the MEA Ramsay Research Fund (RRF) is funding two biomarker studies at the Universities of Oxford and Surrey and we are now considering a third application. All of these studies are using blood samples from the ME Biobank – where the basic running costs are provided by the MEA RRF.
A diagnostic biomarker for ME/CFS has to be both sensitive (i.e. it has to be positive in a very percentage of people) and specific (ie not found in any other conditions with similar symptoms)
So finding a unique biomarker is not an easy task!
This study, has focussed on an abnormality involving a chemical called sphingomyelin phosphodiesterase acid-like 3B* (SMPDL3B). It has produced some interesting preliminary findings which indicate that SMPDL3B is emerging as a potential biomarker for disease severity, that it may be linked to immune system dysfunction, and that this could help with the development of drug treatments for ME/CFS.
However, further work is obviously required to confirm that this abnormality is widely present in ME/CFS and is not present in other conditions that cause ME/CFS type symptoms.
*Additional information for science based readers:
Sphingomyelin phosphodiesterase acid-like 3B (SMPDL3B) is a lipid-modifying enzyme that plays a role in regulating cellular signaling pathways, particularly those involving Toll-like receptors (TLRs) and sphingolipids. It acts as a negative regulator of innate immune signaling and is involved in podocyte function and lipid droplet formation. SMPDL3B is also implicated in various diseases, including kidney diseases and cancer.
Dr Charles Shepherd,
Trustee and Hon. Medical Adviser to the ME Association,
Member of the 2018-2021 NICE guideline on ME/CFS committee,
Member of the 2002 Chief Medical Officer's Working Group on ME/CFS
