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ORIGINAL RESEARCH article
Frontiers in Molecular Biosciences
Sec. Molecular Diagnostics and Therapeutics
Volume 12 - 2025 | doi: 10.3389/fmolb.2025.1582967
Low-Dose Naltrexone restored TRPM3 ion channel function in Natural Killer cells from long COVID patients
Etianne Martini Sasso et al.
8th April 2025
Long COVID is a multisystemic condition that includes neurocognitive, immunological, gastrointestinal and cardiovascular manifestations, independent of the severity or duration of SARS-CoV-2 acute infection. Dysfunctional Transient Receptor Potential Melastatin 3 (TRPM3) ion channels are associated with long COVID pathophysiology due to a reduced calcium (Ca 2+ ) influx, negatively impacting cellular processes in diverse systems. Accumulating evidence suggests the potential therapeutic benefits of low-dose naltrexone (LDN) for people suffering from long COVID. Our study aimed to investigate treatment efficacy with LDN in restoring the TRPM3 ion channel function in natural killer (NK) cells from long COVID patients. NK cells were isolated from nine people with long COVID, nine healthy controls and nine people with long COVID taking LDN (3 -4.5 mg/day). Electrophysiological experiments were used to assess TRPM3 ion channel functions modulated with pregnenolone sulfate and ononetin. The findings from this current research are the first to demonstrate that long COVID patients treated with LDN have restored TRPM3 ion channel function and also validate previous findings of TRPM3 ion channel dysfunction in NK cells from people with long COVID not on treatment. There was no significant difference in TRPM3 currents between long COVID patients taking LDN and HC in either PregS-induced current amplitude (p>0.9999) or resistance to ononetin (p>0.9999). Overall, our findings support LDN as a potentially beneficial treatment for long COVID patients by restoring TRPM3 ion channel function and reestablishing adequate Ca 2+ influx for homeostatic cellular processes to occur.