Decoding m6A RNA methylation in kidney disorders: from molecular insights to therapeutic strategies

Abstract

N⁶-methyladenosine (m⁶A), the most abundant internal modification in eukaryotic messenger RNA (mRNA) and long noncoding RNA (lncRNA), is dynamically modulated by methyltransferases ("writers"), demethylases ("erasers"), and binding proteins ("readers"). As a central epitranscriptomic regulator, m⁶A governs RNA stability, splicing, translation, and degradation, thereby orchestrating a wide range of physiological and pathological pathways. Accumulating evidence has underscored its pivotal involvement in the pathogenesis of kidney disorders. This review delineates the regulatory landscape of m⁶A methylation across various kidney diseases, with emphasis on diabetic nephropathy (DN), acute kidney injury (AKI), chronic kidney disease (CKD), focal segmental glomerulosclerosis (FSGS), lupus nephritis (LN), hyperuricemic nephropathy (HN), autosomal dominant polycystic kidney disease (ADPKD), and clear cell renal cell carcinoma (ccRCC). Disease-specific alterations in m⁶A levels and the expression patterns of core regulators, including METTL3, METTL14, FTO, ALKBH5, YTH domain proteins, and IGF2BPs, are systematically summarized. By elucidating their roles in inflammation, fibrosis, apoptosis, and metabolic imbalance, this review highlights the translational potential of m⁶A-centric interventions and offers novel insights into epitranscriptomic regulation within renal pathophysiology.

Keywords: Clinical significance; Expression profiles; Kidney diseases; Regulatory mechanisms; m6A modification.

Fig. 1

Dysregulated m⁶ A RNA methylation in kidney diseases. In kidney diseases, alterations in m⁶A methylation and its regulatory machinery play pivotal roles in disease progression via multiple mechanisms. Overexpression of METTL3 and IGF2BP3, along with reduced activity of METTL14 or FTO, have been identified in conditions such as DN, AKI, CKD, FSGS, LN, HN, ADPKD, and ccRCC. These disruptions result in abnormal m⁶A modification patterns, affecting critical pathways like inflammation, fibrosis, EMT, autophagy dysregulation, ferroptosis, and mitochondrial dysfunction. Targeting the m⁶A modification system presents a promising therapeutic avenue for mitigating renal damage and halting disease progression

Fig. 2

Regulatory mechanisms of m⁶A methylation dysregulation in DN. In DN, dysregulated m⁶A methylation accelerates disease progression through interconnected pathways that mediate podocyte injury, autophagy dysfunction, tubular impairment, immune activation, and fibrotic remodeling. In podocytes, METTL3 upregulates m⁶A methylation of TIMP2 mRNA via IGF2BP2, activating Notch3/4 signaling. Concurrently, METTL3 enhances YTHDF2-mediated degradation of circ_0000953, impairing miR-665-3p-ATG4B-dependent autophagy. Hyperglycemic conditions suppress METTL3 and IGF2BP2, leading to downregulation of RNF183 and disruption of PKM2 ubiquitination. FTO overexpression stabilizes ACC1 mRNA through YTHDF2 while destabilizing SAA2 to activate NF-κB signaling. In TECs, METTL14 downregulation inhibits PTEN, activating the PI3K/Akt-HDAC5 axis. Additionally, WTAP facilitates m⁶A modification and IGF2BP1-mediated stabilization of NLRP3 mRNA, promoting pyroptosis and inflammation. In the interstitial compartment, SP1 transcriptionally activates circUBXN7, which forms a positive feedback loop with IGF2BP2 to drive macrophage infiltration and fibrosis. FTO also regulates Npas2 mRNA methylation and stability via Prrc2a, enhancing HIF-1α signaling and mitigating M1 macrophage-driven inflammation and glycolysis. SP1: specificity protein 1, HDAC5: Histone Deacetylase 5, TIMP2: Tissue Inhibitor of Metalloproteinases 2, RNF183: Ring Finger Protein 183, PTEN: Phosphatase and Tensin Homolog, NLRP3: NOD-like receptor family pyrin domain containing 3, ACC1: Acetyl-CoA Carboxylase 1, PKM2: Pyruvate Kinase M2, ATG4B: Autophagy Related 4B Cysteine Peptidase

Fig. 3

Regulatory roles of m⁶A RNA methylation in AKI. In AKI, METTL3 is consistently upregulated across various models, promoting m⁶A modification and IGF2BP2-mediated stabilization of Table 3 mRNA, thereby activating TGF-β-driven inflammation. METTL3 also enhances MDM2 mRNA methylation, which is translated via YTHDF1, leading to p53 degradation and subsequent activation of LMNB1. Additionally, METTL3 stabilizes mmu-lncRNA 121,686 and hsa-lncRNA 520,657, which act as sponges for miR-328-5p, derepressing HtrA3 expression and triggering tubular cell apoptosis. METTL3 further facilitates the AKI-CKD transition by stabilizing SREBP1c mRNA, which represses YME1L1, impairing OPA1-mediated mitochondrial dynamics. ZC3H13, another m⁶A writer, is upregulated in TECs during AKI and promotes NABP1 mRNA methylation and stabilization via IGF2BP1. Among the erasers, FTO is downregulated in sepsis-induced AKI, resulting in increased SNHG14 stability and activation of miR-373-3p-ATG7-mediated autophagy and apoptosis. ALKBH5 demethylates CCL28 mRNA in I/R injury, limiting Treg recruitment via IGF2BP2-dependent recognition; inhibiting ALKBH5 enhances CCL28 stability and attenuates inflammation. As a reader, IGF2BP1 stabilizes E2F1 mRNA, promoting MIF expression and NLRP3 inflammasome activation, leading to pyroptosis. YTHDF1, elevated in TECs under stress, facilitates stress granule formation and protects survival-related transcripts such as SPHK1, mitigating tubular injury associated with AKI

Fig. 4

m⁶A methylation-mediated epitranscriptomic regulation of CKD and renal fibrosis. In CKD, m⁶A dysregulation promotes fibrogenesis through modulation of EMT, immune signaling, autophagy, and mitochondrial homeostasis. METTL3 is upregulated in TGF-β-stimulated HK-2 cells, UUO and UIRI mouse models, and IgA nephropathy biopsies, correlating with proteinuria and tubulointerstitial fibrosis. Mechanistically, METTL3 enhances m⁶A modification of NET1 and β-catenin mRNAs, stabilizing these transcripts via IGF2BP3 and activating profibrotic signaling. METTL3 also stabilizes EVL mRNA through IGF2BP2, impairing Smad7-mediated inhibition of TGF-β/Smad3 signaling. In CAR, METTL3 promotes M2 macrophage-driven mesenchymal transition (MMT) via stabilization of Smad3 mRNA; METTL3 knockout or STM2457 treatment reverses fibrosis. METTL3 additionally enhances m⁶A methylation of cGAS and STING1, amplifying inflammatory signaling through the cGAS-STING pathway. FTO, upregulated in UUO and TGF-β-treated TECs, stabilizes RUNX1 mRNA, activating the PI3K/AKT pathway to promote EMT. In contrast, Cana suppresses FTO, enhancing SQSTM1 mRNA stability, restoring FAO through degradation of STAT6, and reducing fibrosis. In aging kidneys, reduced METTL14 levels decrease m⁶A modification of TUG1, destabilizing the lncRNA and impairing PGC-1α-mediated mitochondrial quality control via IGF2BP2