PKM2: A Potential Regulator of Rheumatoid Arthritis via Glycolytic and Non-Glycolytic Pathways

Abstract

Immunometabolism provides a new perspective on the pathogenesis of rheumatoid arthritis (RA). In recent years, there have been investigations focusing on the role of intracellular glucose metabolism in the pathogenesis of RA. Previous studies have shown that glycolysis of synovial tissue is increased in RA patients, while glycolysis inhibitors can significantly inhibit synovitis. Pyruvate kinase (PK) is a key enzyme in glycolysis, catalyzing the final rate-limiting step in the process. An isoform of PK, PKM2, provides favorable conditions for the survival of tumor cells via its glycolytic or non-glycolytic functions and has become a potential therapeutic target in tumors. RA synovium has the characteristic of tumor-like growth, and, moreover, increased expression of PKM2 was identified in the synovial tissue of RA patients in recent studies, indicating the underlying role of PKM2 in RA. PKM2 has potential value as a new therapeutic target or biomarker for RA, but its exact role in RA remains unclear. In this review, the properties of PKM2 and existing research concerning PKM2 and RA are thoroughly reviewed and summarized, and the possible role and mechanism of PKM2 in RA are discussed.

Disease-Specific Autoantibodies Induce Trained Immunity in RA Synovial Tissues and Its Gene Signature Correlates with the Response to Clinical Therapy

“…For example, Ciurtin et al used proton magnetic resonance spectroscopy (MRS) and reported elevated lactate and diminished glucose concentration in synovial fluids, which suggested increased glycolytic activity in synovia [ 47 ]. In the present study, several rate-limiting glycolytic enzymes (i.e., HK3, PFKP, ENO, and PKM2) were upregulated in the cIgG-trained monocytes, which has also been demonstrated in RA inflammatory macrophages [ 14 , 15 ]. Moreover, the Akt-mTOR-HIF1 α signaling pathway-dependent induction of aerobic glycolysis represents a metabolic basis for trained immunity [ 3 ].…”

“…Furthermore, etanercept and adalimumab can downregulate histone tail trimethylation and histone 3 and 4 acetylation at the promoter region of CCL2 (MCP-1) in monocytes, which correlates with the disease activity in RA [ 13 ]. Moreover, glycolysis in RA synovial macrophages is upregulated, as are the rate-limiting enzymes (e.g., pyruvate kinase (PKM) and hexokinase (HK)), which present as signs of increased metabolic activity [ 14 , 15 ]. However, the underlying mechanism of trained immunity in RA remains unclear.…”

Deoxyshikonin Inhibits Viability and Glycolysis by Suppressing the Akt/mTOR Pathway in Acute Myeloid Leukemia Cells

“…Pyruvate kinase (PK) is a rate-limiting glycolytic enzyme. Pyruvate kinase M1 (PKM1) is expressed in normal differentiated tissues, whereas pyruvate kinase M2 (PKM2) is expressed in cancer cells, leading to increased glycolysis (14). As we all know, the protein kinase B (Akt)/mammalian target of rapamycin (mTOR) pathway widely existing in cells is one of the most important survival signaling pathways that participate in the regulation of diverse physiological processes, such as cell growth, apoptosis, and metabolism (15).…”

Human herpesvirus 6A promotes glycolysis in infected T cells by activation of mTOR signaling

“…We also found that HHV-6A have no obvious effect on the expression of ENO1 and PKM2 which control the final steps of glycolysis. PKM2 is the rate-limiting enzyme in the last stage of the glycolytic pathway and when its catalytic rate is lower than the upstream glycolytic rate, phosphoenolpyruvate (PEP) and its upstream glycolytic intermediates may accumulate for the synthesis of macromolecules [61]. Thus, we speculate that during HHV-6 infection there will be an accumulation of glycolytic intermediates which can be used for the biosynthesis of lipids, nucleotides, and proteins required for rapidly virus reproduction.…”