In a groundbreaking study published in Cell Death Discovery, researchers have unveiled a novel molecular mechanism that propels the pathogenesis of rheumatoid arthritis (RA) through metabolic reprogramming of key synovial cells. This investigation sheds new light on how the ubiquitin-specific protease 5 (USP5) orchestrates the glycolytic activity in fibroblast-like synoviocytes (FLSs) by stabilizing the METTL14/m^6A/GLUT1 axis, a previously underexplored regulatory pathway central to RA progression. The implications of this discovery could redefine therapeutic approaches, targeting cellular metabolism to alleviate chronic inflammation and tissue destruction characteristic of RA.
Rheumatoid arthritis is a debilitating autoimmune disorder marked by persistent inflammation primarily in synovial joints, leading to cartilage breakdown, bone erosion, and severe morbidity. Key players in RA are the fibroblast-like synoviocytes, which become aberrantly activated and aggressively proliferate within the synovium, fueling inflammation and joint damage. Previous research has established that these FLSs exhibit a metabolic shift towards glycolysis—a process by which glucose is fermented to support energy requirements even in oxygen-rich conditions, reminiscent of the Warburg effect observed in cancer cells. However, the upstream regulators driving this metabolic rewiring in RA have remained elusive until now.
The latest findings highlight USP5 as a pivotal molecular switch that facilitates the metabolic reprogramming of FLSs. USP5 is a deubiquitinating enzyme known for its role in removing ubiquitin moieties from specific substrate proteins, thus preventing their proteasomal degradation. Through a sophisticated series of biochemical assays and molecular analyses, the research team delineated how USP5 interacts with METTL14, an essential component of the N6-methyladenosine (m^6A) RNA methyltransferase complex. This interaction leads to enhanced stability of METTL14, thereby potentiating m^6A modification of target mRNAs implicated in the metabolic machinery of the cell.
m^6A modification, the most prevalent internal mRNA modification in eukaryotic cells, regulates RNA stability, splicing, transport, and translation efficiency. By preserving METTL14 from degradation, USP5 indirectly influences the m^6A epitranscriptomic landscape within FLSs. The study reveals that this epigenetic modification increases the expression of GLUT1, the primary glucose transporter upregulated in RA FLSs, facilitating elevated glucose uptake and glycolytic flux. This axis—USP5 stabilizing METTL14, which enhances m^6A modification and consequently upregulates GLUT1—constitutes a critical driver of the metabolic phenotype seen in RA synoviocytes.
Importantly, the authors provide evidence that disrupting this pathway can attenuate the glycolytic activity of FLSs, offering a potential avenue for therapeutic intervention. In vitro knockdown experiments targeting USP5 resulted in decreased METTL14 protein levels, reduced m^6A modification on GLUT1 mRNA, and diminished GLUT1 expression. This cascade culminated in lowered glucose metabolism and inhibited FLS proliferation and inflammatory cytokine production, underscoring the centrality of the USP5/METTL14/m^6A/GLUT1 axis in RA pathophysiology.
The research team’s meticulous approach extended beyond cellular models. Using synovial tissue samples from RA patients, they confirmed that USP5 and METTL14 expression levels are markedly elevated in inflamed joints compared to healthy controls. Correspondingly, GLUT1 was found to be significantly upregulated, correlating with disease severity and markers of inflammation. These findings highlight the clinical relevance of the identified pathway and posit that targeting USP5 might disrupt the vicious cycle of inflammation and metabolic dysregulation in RA.
From a broader perspective, this study exemplifies the emerging concept that metabolic reprogramming is not merely a consequence but a driver of inflammatory diseases. By elucidating the mechanistic underpinnings of FLS glycolysis control via epitranscriptomic regulation, the investigation bridges the fields of immunometabolism and RNA biology, promising fresh insights into chronic autoimmune disorders. Therapeutic strategies aiming to inhibit USP5 or modulate m^6A methylation might offer more selective and effective disease-modifying agents with potentially fewer systemic side effects than conventional immunosuppressants.
Moreover, the role of deubiquitinating enzymes such as USP5 in controlling m^6A writers adds a new dimension to the intricate post-translational and epigenetic regulation in immune cells and inflamed tissues. The crosstalk between ubiquitination and RNA methylation as unveiled in this study may inspire a wave of research exploring similar mechanisms in other autoimmune or inflammatory contexts. It also opens the door to drug discovery programs focusing on small molecule inhibitors or degraders of USP5, some of which might already be in developmental pipelines owing to the enzyme’s importance in cancer biology.
An intriguing aspect of the findings is how the altered metabolic state of FLSs perpetuates joint inflammation through enhanced production of pro-inflammatory mediators. Increased glycolysis fuels biosynthetic and energy-demanding pathways needed for sustained synovial hyperplasia, pannus formation, and secretion of cytokines such as TNF-α and IL-6. Blocking the metabolic reprogramming cascade might thus concurrently impede both the hyperproliferative behavior of synoviocytes and the inflammatory milieu, presenting a two-pronged strategy against RA’s hallmark features.
Looking forward, further pre-clinical studies employing animal models of RA are warranted to evaluate the therapeutic efficacy and safety of targeting USP5. Additionally, the interplay between this axis and other known RA signaling pathways, including hypoxia-inducible factors and nuclear factor-kappa B, remains to be investigated. Such integrative analyses could refine the understanding of disease networks and identify synergistic targets. The development of biomarkers based on USP5/METTL14 activity or m^6A signatures in synovial fluids might also enhance diagnosis and monitoring of treatment responses.
Overall, the reported research advances a paradigm shift by aligning post-translational regulation, RNA epigenetics, and immunometabolism into a coherent narrative explaining RA pathology. The discovery that USP5 stabilizes METTL14 to promote an m^6A-dependent upregulation of GLUT1-mediated glycolysis illuminates a previously uncharted territory of molecular crosstalk crucial to chronic joint inflammation. Such insights invigorate hope for novel interventions capable of not only halting disease progression but also restoring joint homeostasis and function.
As rheumatoid arthritis continues to impose a heavy burden globally, innovations that decipher the cellular and molecular intricacies of its pathogenesis are urgently needed. This study exemplifies the power of merging cutting-edge molecular biology tools with clinical relevance to uncover disease mechanisms. By targeting the metabolic engine run by USP5 and the METTL14/m^6A pathway, researchers may have unlocked a promising new front in the battle against autoimmune arthritis—one fueled by molecular precision and potential for transformative impact.
Subject of Research: Mechanistic exploration of how USP5 modulates glycolysis in fibroblast-like synoviocytes through stabilizing the METTL14/m^6A/GLUT1 molecular axis in rheumatoid arthritis.
Article Title: USP5 promotes glycolysis of fibroblast-like synoviocytes by stabilizing the METTL14/m^6A/GLUT1 axis in rheumatoid arthritis.
Article References:
Li, X., Ling, M., Wen, Z. et al. USP5 promotes glycolysis of fibroblast-like synoviocytes by stabilizing the METTL14/m^6A/GLUT1 axis in rheumatoid arthritis. Cell Death Discov. (2025). https://doi.org/10.1038/s41420-025-02890-2
Image Credits: AI Generated
