s (79), can reduce cholesterol and fatty acid biosynthesis and atherogenic hyperlipidemia in animal models, suggesting that azathioprine could possess a equivalent impact (80). SREBP-1 also reduces proinflammatory signaling and modulates macrophage phagocytosis (81, 82), additional pathways that may very well be impacted by the inhibition of this transcription element. Methotrexate, sulfasalazine, and leflunomide. Methotrexate suppresses lymphocyte proliferation and SIRT2 list cytokine production and increases apoptosis through multiple metabolic pathways (Table 2). NPY Y2 receptor drug Individuals with RA have atypically reduced lipid levels thinking about their increased CVD danger (14); in line with this, current studies show that methotrexate increases total cholesterol and LDL when minimizing CVD danger (83), potentially by restoring normal lipoprotein metabolism (84, 85), while decreased proinflammatory cytokine levels and associated inflammation are also likely to play a function (86). The antiinflammatory mechanisms of sulfasalazine are also thought to possess 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 are much less toxic, have fewer adverse effects, and have improved specificity to proteins and signaling pathways linked with illness pathogenesis (96). An array of tsDMARDs exist targeting key proinflammatory signaling pathways which can be stimulated by inflammatory mediators (cytokines, chemokines, growth elements, and antigens), which includes JAK, MAPK, NF-B, and spleen-associated tyrosine kinase (SYK)/Bruton’s tyrosine kinase (BTK) pathways (refs. 968 and Table three). The complete impact of inhibition of these pathways on specific metabolic mechanisms is unclear but likely plays an important part inside the functionality of certain tsDMARDs. Additionally, crosstalk amongst many signaling pathways adds complexity to therapeutic strategies; for example, NF-B target genes can inhibit MAPK signaling (99).JAK inhibitors JAK inhibitors block cell signaling by means of the JAK/STAT pathway (Table 3) but in addition have cell metabolic effects (which includes decreased mitochondrial membrane potential, mitochondrial mass, and ROS and inhibition of metabolic genes in synovial tissue) (100) and modify systemic lipid metabolism. Tofacitinib and baricitinib drastically elevated HDL-C and LDL-C compared with baseline and other DMARD therapies alone in randomized controlled trials in RA and SLE (10106), an effect reversed by statins (107). JAK inhibitors also boost HDL function by increasing the activity of lecithin-cholesterol acyltransferase (LCAT; an enzyme that converts free cholesterol to cholesterol esters and supports cholesterol efflux to lipoproteins), thereby rising HDL efflux capacity (refs. 103, 106, and Figure 1C). Other effects for example alterations in lipoprotein size and content happen to be described (103, 108); thus, these therapies may contribute to drug-induced dyslipidemia and exacerbate the lipid imbalances currently associatedJ Clin Invest. 2022;132(2):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 two. Mechanisms of action of existing standard therapies used in AIRDs (part two) Drug Mechanisms/effects Effects on lipid metabolismMycophenolic acid (the active metabolite mycophenolate mofetil) activates PPAR and increases intracellular lipids such as fatty acids, cholesterol, and phosphatidylcholine in vitro.R