unknown (ref. 92 and Table 2). Cyclophosphamide. Cyclophosphamide can lower LDL and VLDL levels and boost acetate (a lipid Nav1.1 Formulation metabolism by-product) in lupus nephritis individuals (93). Even so, acrolein, a cyclophosphamide metabolite (Table 1), can outcome in dose-related cardiotoxicity, that is a limiting factor for cyclophosphamide use (94). Acrolein alters levels of heart fatty acid inding proteins, which deplete antioxidants and ATP levels via altered mitochondrial -oxidation, thereby minimizing the cellular energy pool. Together, these metabolic modifications boost apoptosis in cardiomyocytes and may result in heart failure and myocardial infarction (94). These off-target metabolic effects call for close cyclophosphamide dose monitoring and modification in individuals with AIRDs. There are handful of other reports that cyclophosphamide influences metabolite levels in AIRDs (95).It has also been shown to disrupt lysosomal membranes; thus, hydroxychloroquine could also mediate its effects in AIRDs by modifying lipid raft ediated S1PR4 custom synthesis immune cell signaling, which can in turn modulate immune cell function (refs. 9, 68, and Figure 1A). Calcineurin inhibitors. Calcineurin inhibitors (cyclosporin, voclosporin, tacrolimus) block T cell signaling and activation (Table 1) but additionally have noteworthy off-target effects, like impairment of endothelial cell function connected with COX-2 inhibition and decreased production of prostaglandin E2 (69) and dyslipidemia (enhanced total cholesterol, LDL-C, triglycerides, and apolipoprotein B) (70, 71). Many mechanisms could contribute to altered lipid levels, which includes decreased hepatic LDL-C clearance and elevated cholesterol biosynthesis via the HMG-CoA pathway mediated by inhibition of 27-hydroxycholesterol, an oxysterol that inhibits cholesterol metabolism through HMG-CoA (ref. 72 and Figure 1C). Interestingly, voclosporin, recently approved for use in adult lupus nephritis, shows a considerable reduction in total cholesterol and LDL-C, potentially because of its superior antiinflammatory properties (73). Cyclosporin also inhibits bile acid synthesis through 26-hydroxylase and could decrease triglyceride degradation by inhibiting lipoprotein lipase activity (71, 74). Therefore, while calcineurin inhibitors are favorable in AIRDs, additional mechanistic analysis is necessary to assess the antiinflammatory added benefits against the off-target effects of blocking basic metabolic processes. Mycophenolate mofetil and azathioprine. Mycophenolate mofetil (MMF) and azathioprine inhibit cellular proliferation through inhibition of purine nucleotide synthesis pathways (ref. 75 and Table two). Mycophenolic acid (the active metabolite of MMF) can also activate PPAR (76) and improve intracellular lipids including fatty acids, cholesterol, and phosphatidylcholine in vitro (77). Such metabolic dysregulation could contribute to MMF function by way of disruption of cell signaling and membrane integrity. Yet another study shows that azathioprine lowered abnormally upregulated cellular cholesterol/lipid biosynthesis and uptake and induced ER stress and apoptosis in glioblastoma; this effect was most likely mediated by blocking of EGFR/AKT/SREBP-1 signaling and not through the common ABCA1-mediated cholesterol efflux through the LXR transcription aspect, as neither LXR nor ABCA1 levels have been altered by azathioprine (78). Interestingly, small-molecule inhibitors of sterol regulatory element inding protein (SREBP) such as betulin, along with their antitumoral effect
