s (79), can minimize cholesterol and fatty acid biosynthesis and atherogenic hyperlipidemia in animal models, suggesting that azathioprine could PKD1 Biological Activity possess a related effect (80). SREBP-1 also reduces proinflammatory signaling and modulates macrophage phagocytosis (81, 82), added pathways that could be impacted by the inhibition of this transcription issue. Methotrexate, sulfasalazine, and leflunomide. Methotrexate suppresses lymphocyte proliferation and cytokine production and increases apoptosis via several metabolic pathways (Table two). Patients with RA have atypically lowered lipid levels considering their improved CVD danger (14); in line with this, recent studies show that methotrexate increases total cholesterol and LDL when reducing CVD risk (83), potentially by restoring regular lipoprotein metabolism (84, 85), although lowered proinflammatory cytokine levels and linked 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 utilised increasingly to treat AIRDs due to the fact 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 essential proinflammatory signaling pathways which might be stimulated by inflammatory mediators (cytokines, chemokines, growth variables, 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 complete effect of inhibition of these pathways on distinct metabolic mechanisms is unclear but probably plays an important role inside the functionality of certain tsDMARDs. Moreover, crosstalk involving various signaling pathways adds complexity to therapeutic methods; one example is, 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 additionally have cell metabolic effects (which includes decreased mitochondrial membrane potential, mitochondrial mass, and ROS and inhibition of metabolic genes in synovial tissue) (one hundred) and modify systemic lipid metabolism. Tofacitinib and baricitinib drastically enhanced 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 strengthen 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 increasing HDL efflux capacity (refs. 103, 106, and Figure 1C). Other effects including alterations in lipoprotein size and content material have been described (103, 108); consequently, these therapies might contribute to Mite Compound 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 two. Mechanisms of action of current standard therapies made use of in AIRDs (part 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