total cholesterol and LDL whilst minimizing CVD threat, potentially by restoring regular lipoprotein metabolism, that is dysregulated in RA.835, 211SulfasalazineCardioprotective effects potentially mediated via scavenging of oxygen radicals major to decreased lipid peroxidation; inhibition of arachidonic acid metabolism by means of COX enzymes, resulting in lowered platelet aggregation; and inhibition of NF-B signaling. Can induce ferroptosis. Regulates abnormal expression of lipid rafts in B cells from SLE sufferers. Reduces LDL and VLDL levels and increases acetate (a lipid metabolism by-product) in lupus nephritis. Acrolein induces dose-related cardiotoxicity: alters levels of heart fatty acid inding proteins, which deplete antioxidants and ATP levels by way of altered mitochondrial -oxidation, and reduces the cellular power pool.36, 87Leflunomide Cyclophosphamide220, 221 93, 94, 222Overview in the mechanisms of action of therapies μ Opioid Receptor/MOR custom synthesis utilised for patients with AIRDs and their impact on lipid metabolism pathways. AICAR, 5-aminoimidazole-4carboxamide ribonucleotide transformylase; AMPK, 5-adenosine monophosphate ctivated protein kinase; iNOS, inducible nitric oxide synthase; NFAT, nuclear aspect of activated T cells; NF-B, nuclear element -light-chain-enhancer of activated B cells; PG, prostaglandin; SREBP, sterol regulatory element inding protein.with AIRDs. Previous trials have highlighted issues surrounding the danger of arterial and venous thrombotic events with JAK inhibition, and emerging evidence suggests that this threat is dependent on JAK selectivity and is potentially confounded by indication (109, 110). According to a critique of a randomized controlled trial of tofacitinib versus anti-TNF remedy, the Meals and Drug Administration issued an urgent revision for all JAK inhibitors to include information regarding prospective enhanced risks of really serious heart-related events, cancer, blood clots, and death. These emerging issues aremirrored in suggestions to assess the advantages and dangers for patients just before initiating or continuing JAK inhibitor therapy (111).Targeting the MAPK pathway The MAPK pathway, comprising ERK, JNK, and p38 kinase (p38) (112), regulates cellular function by means of activation of transcription aspects (Table three). Though targeting of MAPKs for example p38 by VX-702 has shown clinical benefit in RA and animal models of SLE, the usage of MAPK inhibitors is confounded by the vast and pleiotropicJ Clin Invest. 2022;132(two):e148552 doi.org/10.1172/JCIR 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 MThe Journal of Clinical InvestigationTable three. Mechanisms of action of tsDMARDs used in AIRDs DrugJAK inhibitorsMechanisms/effectsJAK inhibitors competitively bind to JAK ATP-binding web pages and suppress JAK enzyme activity. JAKs are tyrosine kinases that bind to membrane receptors stimulated by inflammatory molecules including interferon, which, upon activation, phosphorylate STAT transcription components, which translocate to the nucleus and promote the expression of inflammatory genes. JAK inhibitors block signaling by way of quite a few cytokine and hematopoietic development issue receptors. Some SLE patients having a STAT4 danger allele responded superior to JAK inhibitors. JAK/STAT signaling plays a basic role in metabolic homeostasis, such as glucose tolerance and insulin sensitivity, within a cell-specific manner; e.g., stimulation of JAK/ STAT3 signaling results in improved translocation of GLUT-4 towards the plasma membrane in p38β Compound skeletal muscle cells, and JAK/STAT2 sign