Principles behind SLE treatment with N-acetylcysteine

Systemic lupus erythematous (SLE) is a multisystem chronic autoimmune disease in which disrupted molecular pathways lead to multiple clinical manifestations. Currently approved treatments include hydroxychloroquine, some immunosuppressive medications, and some biologics. They all come with a range of side effects. N-acetylcysteine (NAC) is an antioxidant that has shown potential benefits in SLE patients without having major side effects. The following review highlights the molecular mechanisms behind the therapeutic effect of NAC in SLE patients. A higher-than normal mitochondrial transmembrane potential or mitochondrial hyperpolarization (MHP) was found in lymphocytes from SLE patients. MHP is attributed the blocked electron transport, and it is associated with the depletion of ATP and glutathione and the accumulation of oxidative stress-generating mitochondria due to diminished mitophagy. Comprehensive metabolome analyses identified the accumulation of kynurenine as the most predictive metabolic biomarker of lupus over matched healthy subjects. Cysteine is the rate-limiting constituent in the production of reduced glutathione, and it can be replaced by its precursor NAC. Kynurenine accumulation has been reversed by treatment with NAC but not placebo in the setting of a double-blind placebo-controlled clinical trial of 3-month duration. Mitochondrial oxidative stress and its responsiveness to NAC have been linked to systemic inflammation, gut microbiome changes, and organ damage in lupus-prone mice. Given the unique safety of NAC and chronicity of SLE, the clinical trial of longer duration is being pursued.