s (79), can lessen cholesterol and fatty acid biosynthesis and atherogenic hyperlipidemia in animal models, suggesting that azathioprine could have a comparable impact (80). PDE2 Formulation SREBP-1 also reduces proinflammatory ROCK1 Molecular Weight signaling and modulates macrophage phagocytosis (81, 82), more pathways that may be affected by the inhibition of this transcription factor. Methotrexate, sulfasalazine, and leflunomide. Methotrexate suppresses lymphocyte proliferation and cytokine production and increases apoptosis via multiple metabolic pathways (Table 2). Sufferers with RA have atypically lowered lipid levels thinking of their improved CVD risk (14); in line with this, current studies show that methotrexate increases total cholesterol and LDL while reducing CVD risk (83), potentially by restoring typical lipoprotein metabolism (84, 85), although lowered proinflammatory cytokine levels and related inflammation are also likely to play a role (86). The antiinflammatory mechanisms of sulfasalazine are also thought to have cardioprotective effects (87), potentiallyTarget synthetic DMARDsTarget synthetic DMARDs (tsDMARDs) are small-molecule inhibitors used increasingly to treat AIRDs given that they’re less toxic, have fewer adverse effects, and have increased specificity to proteins and signaling pathways linked with illness pathogenesis (96). An array of tsDMARDs exist targeting key proinflammatory signaling pathways which might be stimulated by inflammatory mediators (cytokines, chemokines, development elements, and antigens), like JAK, MAPK, NF-B, and spleen-associated tyrosine kinase (SYK)/Bruton’s tyrosine kinase (BTK) pathways (refs. 968 and Table 3). The complete effect of inhibition of these pathways on particular metabolic mechanisms is unclear but likely plays an important function within the functionality of particular tsDMARDs. In addition, crosstalk involving several signaling pathways adds complexity to therapeutic tactics; for 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 three) but in addition have cell metabolic effects (like 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 substantially enhanced 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 strengthen HDL function by escalating the activity of lecithin-cholesterol acyltransferase (LCAT; an enzyme that converts totally free cholesterol to cholesterol esters and supports cholesterol efflux to lipoproteins), thereby growing HDL efflux capacity (refs. 103, 106, and Figure 1C). Other effects including alterations in lipoprotein size and content happen to be described (103, 108); consequently, these therapies may contribute to drug-induced dyslipidemia and exacerbate the lipid 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 current standard therapies employed in AIRDs (element 2) Drug Mechanisms/effects Effects on lipid metabolismMycophenolic acid (the active metabolite mycophenolate mofetil) activates PPAR and increases intracellular lipids like fatty acids, cholesterol, and phosphatidylcholine in vitro.R