s (79), can lower cholesterol and fatty acid biosynthesis and atherogenic hyperlipidemia in animal models, suggesting that azathioprine could have a equivalent effect (80). SREBP-1 also reduces proinflammatory signaling and modulates macrophage phagocytosis (81, 82), extra pathways that could be affected by the inhibition of this transcription factor. Methotrexate, sulfasalazine, and leflunomide. Methotrexate suppresses lymphocyte proliferation and cytokine production and increases apoptosis through numerous MT1 manufacturer metabolic pathways (Table two). Individuals with RA have atypically decreased lipid levels taking into consideration their increased CVD danger (14); in line with this, current research show that methotrexate increases total cholesterol and LDL when reducing CVD risk (83), potentially by restoring typical lipoprotein metabolism (84, 85), despite the fact that reduced proinflammatory cytokine levels and related inflammation are also probably to play a part (86). The antiinflammatory mechanisms of sulfasalazine are also believed to have cardioprotective effects (87), potentiallyTarget synthetic DMARDsTarget synthetic DMARDs (tsDMARDs) are small-molecule inhibitors utilized increasingly to treat AIRDs because they are much 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 crucial proinflammatory signaling pathways that are stimulated by inflammatory mediators (cytokines, chemokines, growth aspects, and antigens), such as JAK, MAPK, NF-B, and spleen-associated tyrosine kinase (SYK)/Bruton’s tyrosine kinase (BTK) pathways (refs. 968 and Table 3). The full influence of inhibition of these pathways on distinct metabolic mechanisms is unclear but probably plays an essential role within the overall performance of particular tsDMARDs. Moreover, crosstalk amongst different signaling pathways adds complexity to therapeutic methods; for example, NF-B target genes can inhibit MAPK signaling (99).JAK inhibitors JAK inhibitors block cell signaling via the JAK/STAT pathway (Table three) but in addition 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 substantially increased HDL-C and LDL-C compared with baseline as well as other DMARD treatment options alone in randomized controlled trials in RA and SLE (10106), an effect reversed by statins (107). JAK inhibitors also enhance HDL function by increasing the activity of lecithin-cholesterol acyltransferase (LCAT; an enzyme that converts cost-free cholesterol to cholesterol Abl Inhibitor MedChemExpress esters and supports cholesterol efflux to lipoproteins), thereby growing HDL efflux capacity (refs. 103, 106, and Figure 1C). Other effects which include alterations in lipoprotein size and content material have already been described (103, 108); hence, 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 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 existing traditional therapies used in AIRDs (element 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