s (79), can reduce cholesterol and fatty acid biosynthesis and atherogenic hyperlipidemia in animal models, suggesting that azathioprine could have a similar effect (80). SREBP-1 also reduces proinflammatory signaling and modulates macrophage phagocytosis (81, 82), more pathways that may be impacted by the inhibition of this transcription aspect. Methotrexate, sulfasalazine, and leflunomide. Methotrexate suppresses lymphocyte proliferation and cytokine production and increases apoptosis through many metabolic pathways (Table 2). Patients with RA have atypically reduced lipid levels thinking of their elevated CVD threat (14); in line with this, current studies show that methotrexate increases total cholesterol and LDL though minimizing CVD danger (83), potentially by restoring standard lipoprotein metabolism (84, 85), although reduced proinflammatory cytokine levels and related inflammation are also probably to play a role (86). The antiinflammatory mechanisms of sulfasalazine are also believed to SSTR3 drug possess cardioprotective 5-HT4 Receptor Agonist Molecular Weight effects (87), potentiallyTarget synthetic DMARDsTarget synthetic DMARDs (tsDMARDs) are small-molecule inhibitors utilized increasingly to treat AIRDs considering that they’re less toxic, have fewer adverse effects, and have enhanced specificity to proteins and signaling pathways associated with illness pathogenesis (96). An array of tsDMARDs exist targeting essential proinflammatory signaling pathways which can be stimulated by inflammatory mediators (cytokines, chemokines, development factors, and antigens), including JAK, MAPK, NF-B, and spleen-associated tyrosine kinase (SYK)/Bruton’s tyrosine kinase (BTK) pathways (refs. 968 and Table 3). The full effect of inhibition of these pathways on distinct metabolic mechanisms is unclear but most likely plays an essential function inside the performance of distinct tsDMARDs. Moreover, crosstalk among various signaling pathways adds complexity to therapeutic tactics; as an example, NF-B target genes can inhibit MAPK signaling (99).JAK inhibitors JAK inhibitors block cell signaling through the JAK/STAT pathway (Table 3) but additionally have cell metabolic effects (which includes decreased mitochondrial membrane prospective, mitochondrial mass, and ROS and inhibition of metabolic genes in synovial tissue) (one hundred) and modify systemic lipid metabolism. Tofacitinib and baricitinib significantly elevated HDL-C and LDL-C compared with baseline as well as other DMARD remedies 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 rising HDL efflux capacity (refs. 103, 106, and Figure 1C). Other effects such as alterations in lipoprotein size and content have been described (103, 108); as a result, these therapies could 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 existing standard therapies utilized in AIRDs (component two) Drug Mechanisms/effects Effects on lipid metabolismMycophenolic acid (the active metabolite mycophenolate mofetil) activates PPAR and increases intracellular lipids such as fatty acids, cholesterol, and phosphatidylcholine in vitro.R