SMPDL3B a novel biomarker and therapeutic target in myalgic encephalomyelitis, 2025, Moreau, Fluge, Mella et al

[Hutan]

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[SNT Gatchaman]

Comment on “SMPDL3B as a novel biomarker and therapeutic target in myalgic encephalomyelitis” critical considerations on biomarker validation and Supraphysiological drug concentrations (Chen & Yan)

The authors’ approach to validating the 30 ng/mL plasma SMPDL3B threshold exhibits significant methodological circularity [2]: the threshold derived from the Canadian cohort (using MFI-20/SF-36/DSQ questionnaires) was applied without recalibration to the Norwegian cohort with its distinct physician-based severity classification. This introduces inherent circularity in the Canadian cohort validation, as associations (e.g., reported OR = 3.0) were tested using the same data that generated the threshold, artificially strengthening apparent correlations. The subsequent AUC drop (0.84 → 0.73) in the Norwegian cohort further demonstrates reduced generalizability due to mismatched assessment methodologies.

The in vitro demonstration of PI-PLC inhibition by vildagliptin and saxagliptin at 100 µM raises significant translational concerns due to the use of supraphysiological concentrations, which represent a 250-fold excess over therapeutic plasma levels observed in diabetic patients (≤ 0.4 µM) [3]. This methodological approach is further compromised by the absence of cell viability controls, particularly as vildagliptin induced significant reductions in SMPDL3B gene expression at this concentration—an effect that could reflect cytotoxicity rather than specific pharmacological modulation [4]. The paradoxical increase in SMPDL3B expression with linagliptin at 100 µM, attributed to structural differences, similarly lacks validation against cytotoxicity markers or stress-response assays, leaving the mechanistic interpretation ambiguous.