s (79), can reduce cholesterol and fatty acid biosynthesis and atherogenic hyperlipidemia in animal models, suggesting that azathioprine could have a comparable effect (80). SREBP-1 also reduces proinflammatory signaling and modulates macrophage phagocytosis (81, 82), extra pathways that may very well be affected by the inhibition of this transcription element. Methotrexate, sulfasalazine, and leflunomide. Methotrexate suppresses lymphocyte proliferation and cytokine production and increases apoptosis by means of numerous metabolic pathways (Table 2). Patients with RA have atypically decreased lipid levels taking into consideration their enhanced CVD threat (14); in line with this, current research show that methotrexate increases total cholesterol and LDL although lowering CVD risk (83), potentially by restoring regular lipoprotein metabolism (84, 85), though lowered proinflammatory cytokine levels and linked inflammation are also probably to play a part (86). The antiinflammatory mechanisms of sulfasalazine are also thought to have cardioprotective effects (87), potentiallyTarget synthetic DMARDsTarget synthetic DMARDs (tsDMARDs) are small-molecule inhibitors utilized increasingly to treat AIRDs since they’re significantly less toxic, have fewer adverse effects, and have increased specificity to proteins and signaling pathways connected with illness pathogenesis (96). An array of tsDMARDs exist targeting essential proinflammatory signaling pathways that are stimulated by inflammatory mediators (cytokines, chemokines, development MMP-2 list things, and antigens), which includes JAK, MAPK, NF-B, and spleen-associated tyrosine kinase (SYK)/Bruton’s tyrosine kinase (BTK) pathways (refs. 968 and Table 3). The complete impact of inhibition of these pathways on precise metabolic mechanisms is unclear but most likely plays a vital function within the performance of distinct tsDMARDs. Additionally, crosstalk amongst various signaling pathways adds complexity to therapeutic strategies; as an 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 also have cell metabolic effects (including decreased mitochondrial membrane possible, mitochondrial mass, and ROS and inhibition of metabolic genes in synovial tissue) (one hundred) and modify systemic lipid metabolism. Tofacitinib and baricitinib drastically elevated HDL-C and LDL-C compared with baseline and other DMARD remedies alone in randomized controlled trials in RA and SLE (10106), an impact reversed by statins (107). JAK inhibitors also increase HDL function by increasing the activity of lecithin-cholesterol acyltransferase (LCAT; an enzyme that converts totally free cholesterol to cholesterol esters and supports cholesterol efflux to lipoproteins), thereby rising HDL efflux capacity (refs. 103, 106, and Figure 1C). Other effects like alterations in lipoprotein size and content happen to be described (103, 108); consequently, these therapies may perhaps contribute to drug-induced dyslipidemia and exacerbate the lipid imbalances already associatedJ Clin Invest. 2022;132(2):e148552 doi.org/10.1172/JCIThe ADAM17 Inhibitor Species 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 current standard therapies applied in AIRDs (aspect 2) Drug Mechanisms/effects Effects on lipid metabolismMycophenolic acid (the active metabolite mycophenolate mofetil) activates PPAR and increases intracellular lipids which includes fatty acids, cholesterol, and phosphatidylcholine in vitro.R