s (79), can lower cholesterol and fatty acid biosynthesis and atherogenic hyperlipidemia in animal models, suggesting that azathioprine could possess a equivalent effect (80). SREBP-1 also reduces proinflammatory signaling and modulates macrophage phagocytosis (81, 82), more pathways that could possibly be affected by the inhibition of this transcription issue. Methotrexate, sulfasalazine, and leflunomide. Methotrexate suppresses lymphocyte proliferation and cytokine production and increases apoptosis through several metabolic pathways (Table two). Individuals with RA have atypically decreased lipid levels taking into consideration their enhanced CVD danger (14); in line with this, current studies show that methotrexate increases total cholesterol and LDL although minimizing CVD risk (83), potentially by restoring regular lipoprotein metabolism (84, 85), while reduced proinflammatory cytokine levels and linked inflammation are also likely to play a function (86). The antiinflammatory mechanisms of sulfasalazine are also believed to possess cardioprotective SIRT5 Purity & Documentation Effects (87), μ Opioid Receptor/MOR site potentiallyTarget synthetic DMARDsTarget synthetic DMARDs (tsDMARDs) are small-molecule inhibitors utilised increasingly to treat AIRDs given that they may be significantly less toxic, have fewer adverse effects, and have increased specificity to proteins and signaling pathways linked with disease pathogenesis (96). An array of tsDMARDs exist targeting key proinflammatory signaling pathways that are stimulated by inflammatory mediators (cytokines, chemokines, growth variables, 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 full impact of inhibition of those pathways on particular metabolic mechanisms is unclear but probably plays an essential part in the overall performance of certain tsDMARDs. Moreover, crosstalk involving many signaling pathways adds complexity to therapeutic tactics; one example is, NF-B target genes can inhibit MAPK signaling (99).JAK inhibitors JAK inhibitors block cell signaling by means 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 considerably enhanced HDL-C and LDL-C compared with baseline and also other DMARD therapies alone in randomized controlled trials in RA and SLE (10106), an impact reversed by statins (107). JAK inhibitors also enhance HDL function by rising the activity of lecithin-cholesterol acyltransferase (LCAT; an enzyme that converts free of charge cholesterol to cholesterol esters and supports cholesterol efflux to lipoproteins), thereby increasing HDL efflux capacity (refs. 103, 106, and Figure 1C). Other effects which include alterations in lipoprotein size and content material have been described (103, 108); hence, these therapies may well 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 two. Mechanisms of action of existing standard therapies employed 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