Metformin’s activation of AMP-activated protein kinase (AMPK) leads to the inhibition of mTOR (mammalian target of rapamycin), a pivotal regulator of lymphocyte immunometabolism and the equilibrium between pro-inflammatory and anti-inflammatory cell populations within joint tissues. This inhibition results in decreased production of pro-inflammatory Th1 and Th17 cells, along with M1 macrophages, thereby promoting a predominance of anti-inflammatory Treg cells and M2 macrophages. ATP—Adenosine triphosphate, AMP—Adenosine monophosphate, AMPK—AMP-activated protein kinase, mTORC1—Mechanistic target of rapamycin complex 1, mTORC2—Mechanistic target of rapamycin complex 2, MLST8 (MLST8 protein)—mammalian lethal with SEC13 protein 8, PRAS40—Proline-rich AKT substrate 40 kDa, Ras—Rat sarcoma protein, Raf—Rapidly accelerated fibrosarcoma protein, MEK—mitogen-activated protein kinase kinase, ERK—extracellular signal-regulated kinase, RSK—Ribosomal S6 kinase, PI3K—phosphoinositide 3-kinase, Akt—protein kinase B (Akt), TSC1/2—tuberous sclerosis complex 1/2, Rheb—Ras homolog enriched in brain, GDP—Guanosine diphosphate, MSIN1—MAPK (mitogen-activated protein kinase)-interacting protein 1, MLSTS (MLSTS protein)—mammalian lethal with SEC13 protein, Reg A/B (regulatory proteins A/B), GTP—Guanosine triphosphate, Reg C/D (regulatory proteins C/D), Treg—regulatory T cells, M1—M1 macrophages (classically activated macrophages), M2—M2 macrophages (alternatively activated macrophages), Th1—T helper 1 cells, Th17—T helper 17 cells. Figure 2 has been created in BioRender.com (accessed on 2 July 2024).