s (79), can cut down cholesterol and fatty acid biosynthesis and atherogenic hyperlipidemia in animal models, suggesting that azathioprine could have a related impact (80). SREBP-1 also reduces proinflammatory signaling and modulates macrophage phagocytosis (81, 82), additional pathways that could be affected by the inhibition of this transcription issue. Methotrexate, sulfasalazine, and leflunomide. Methotrexate suppresses lymphocyte proliferation and cytokine production and increases apoptosis by way of multiple metabolic pathways (Table two). Patients with RA have atypically reduced lipid levels considering their elevated CVD risk (14); in line with this, recent studies show that methotrexate increases total cholesterol and LDL even though reducing CVD risk (83), potentially by restoring standard lipoprotein metabolism (84, 85), despite the fact that reduced proinflammatory cytokine levels and connected inflammation are also probably to play a role (86). The antiinflammatory mechanisms of sulfasalazine are also believed to have cardioprotective effects (87), potentiallyTarget synthetic DMARDsTarget synthetic DMARDs (tsDMARDs) are small-molecule inhibitors made use of increasingly to treat AIRDs considering the fact that they’re less toxic, have fewer adverse effects, and have increased specificity to proteins and signaling pathways associated with disease pathogenesis (96). An array of tsDMARDs exist targeting important proinflammatory signaling pathways which might be stimulated by inflammatory mediators (cytokines, chemokines, growth variables, and antigens), like JAK, MAPK, NF-B, and spleen-associated tyrosine kinase (SYK)/Bruton’s tyrosine kinase (BTK) pathways (refs. 968 and Table three). The complete effect of inhibition of these pathways on distinct metabolic mechanisms is unclear but probably plays a vital role inside the efficiency of precise tsDMARDs. Furthermore, crosstalk among many signaling pathways adds complexity to therapeutic tactics; by way of example, NF-B target genes can inhibit MAPK signaling (99).JAK inhibitors JAK inhibitors block cell signaling by way of the JAK/STAT pathway (Table 3) but additionally have cell metabolic effects (such as decreased mitochondrial membrane possible, mitochondrial mass, and ROS and inhibition of metabolic genes in synovial tissue) (100) and modify systemic lipid metabolism. Tofacitinib and baricitinib significantly increased HDL-C and LDL-C compared with baseline and also other DMARD treatments alone in randomized controlled trials in RA and SLE (10106), an effect reversed by statins (107). JAK inhibitors also enhance HDL function by PI3KC2β drug growing the activity of lecithin-cholesterol acyltransferase (LCAT; an enzyme that converts free of charge cholesterol to cholesterol esters and supports cholesterol efflux to lipoproteins), thereby growing HDL efflux capacity (refs. 103, 106, and Figure 1C). Other effects for instance alterations in lipoprotein size and content have already been described (103, 108); for that reason, these therapies might contribute to drug-induced dyslipidemia and exacerbate the lipid SSTR2 Formulation imbalances already associatedJ Clin Invest. 2022;132(two):e148552 doi.org/10.1172/JCIThe Journal of Clinical InvestigationR E V I E W S E R I E S : I M M U N O M E TA B O L I S MTable 2. Mechanisms of action of present standard therapies applied in AIRDs (component 2) Drug Mechanisms/effects Effects on lipid metabolismMycophenolic acid (the active metabolite mycophenolate mofetil) activates PPAR and increases intracellular lipids including fatty acids, cholesterol, and phosphatidylcholine in vitro.R