Posttranslational Modifications: Novel Molecular Mechanism and Traditional Chinese Medicine Therapeutic Strategy in IgA Nephropathy
Year: 2026
Type: article
Abstract: INTRODUCTION IgA nephropathy (IgAN), the most common primary glomerulonephritis worldwide, is characterized by the deposition of immune complexes, predominantly containing IgA1, in the glomerular mesangium. Asian patients with IgAN often exhibit more severe clinical presentations and a heightened risk of disease progression. The pathogenesis of IgAN is multifactorial, with the “four-hit hypothesis” representing the most widely accepted model: (1) overproduction of aberrantly glycosylated IgA1 from the intestinal mucosa, (2) formation of immune complexes with specific antibodies, (3) deposition of these complexes in the renal mesangium, and (4) subsequent activation of mesangial cells, leading to kidney injury. As current understanding of IgAN pathogenesis expands, treatment strategies are evolving from traditional nonspecific immunosuppression towards targeted therapies. However, achieving optimal therapeutic outcomes remains a challenge. Budesonide, while recommended for adult patients with IgAN at risk of progression, is limited by adverse hormonal effects, such as edema and hypertension.[1] Therefore, continued investigation into novel pathogenic mechanisms and therapeutic strategies for IgAN is critically important. POSTTRANSLATIONAL MODIFICATIONS (PTMs) IN IGAN Studies have demonstrated that PTMs contribute significantly to key steps in the four-hit hypothesis of IgAN. PTMs, covalent chemical alterations occurring after protein translation, are mediated by specific enzymes that attach chemical moieties (e.g., glycosyl, sialyl, and phosphoryl groups) to amino acid side chains. By altering protein structure and physicochemical properties, PTMs modulate diverse cellular processes, including protein localization, stability and activity and protein-protein interactions.[2] The O-glycans of circulating IgA1 in IgAN consist of N-acetylgalactosamine (GalNAc) and β1, 3-linked galactose. O-glycosylation represents a fundamental protein translational modification (PTM) characterized by the enzymatic attachment of carbohydrate moieties (most commonly GalNAc) to the hydroxyl groups of serine or threonine residues through α- or β-glycosidic linkages in proteins. Aberrant glycosylation, particularly O-glycosylation defects in the IgA1 hinge region, constitutes the fundamental mechanism underlying the formation of pathogenic galactose-deficient IgA1. Reduced activity of core 1 beta1, 3-galactosyltransferase 1 impedes the normal attachment of galactose to GalNAc, resulting in the formation of an aberrant galactose-deficient structure. Recent findings have further highlighted the role of aberrant O-glycosylation, demonstrating that deletion of the N-acetylgalactosamine transferase 14 gene (encoding the N-acetylgalactosamine transferase 14 enzyme, which mediates IgA1 O-glysylation), promotes IgA1 production and mesangial deposition while also affecting mucosal immunity and B cell homing.[3] The O-glycans of IgA1 can also undergo sialylation, a critical glycosylation modification involving enzymatic attachment of sialic acid residues via α-glycosidic bonds to terminal glycan structures (e.g., galactose and GalNAc) on glycoproteins and glycolipids. Importantly, the sialyltransferase ST6GalNAc-II catalyzes the attachment of sialic acid to exposed GalNAc residues, which enhances the antigenicity of galactose-deficient IgA1 and stabilizes immune complexes. This modification facilitates their escape from clearance mechanisms and promotes the formation of pathogenic immune complexes, ultimately contributing to the deterioration of renal function in IgAN.[4] Furthermore, emerging evidence suggests a correlation between aberrant IgA1 N-glycosylation and declining renal function in IgAN, although the underlying molecular mechanisms warrant further investigation.[5] In the fourth hit, deposited immune complexes activate mesangial cells, triggering protein phosphorylation as a key intracellular signaling mechanism. Phosphorylation is a PTM process in which a phosphate group is covalently attached to specific amino acid residues of proteins, lipids, or other biomolecules, catalyzed by kinases and reversible by phosphatases. For example, phosphorylation-mediated activation of nuclear factor kappa-B (NF-κB) induces a proinflammatory phenotype in human renal mesangial cells by promoting the production of proinflammatory cytokines and chemokines (including Interleukin-6 [IL-6], C-X-C motif chemokine ligand 10 [CXCL10], and C-C motif chemokine ligand 5 [CCL5]), ultimately leading to renal tissue damage.[6] Therefore, glycosylation modifications directly participate in the generation of pathogenic antigens, whereas phosphorylation drives the amplification of inflammatory responses and renal injury progression. D-LACTYLATION: A NEWLY DISCOVERED PTM POTENTIALLY CONTRIBUTING TO IGAN In IgAN, gut dysbiosis and increased intestinal permeability lead to significant elevation of peripheral blood D-lactate levels. D-lactate primarily originates from gastrointestinal bacteria and exogenous sources, with negligible production within tissues. Given the diverse regulatory roles of D-lactate in various physiological and pathological processes, and the close association between D-lactylation modification and D-lactate metabolism, we hypothesize that D-lactylation modification may play a role in IgAN pathogenesis. To address this, we performed a preliminary study confirming the presence of altered D-lactylation patterns in the kidneys of patients with IgAN. Compared to controls, IgAN mice exhibited markedly increased D-lactylation specifically in the renal cortex. Integrated D-lactylation proteomics and conventional proteomics identified 67 D-lactylation sites, corresponding to 60 proteins, that were significantly upregulated in the renal cortex of the IgAN mice. In vitro, costimulation of human mesangial cells with D-lactate and polymeric IgA1 (pIgA1) synergistically enhanced cell activation, proliferation, and inflammatory responses, along with increased D-lactylation, compared to pIgA1 stimulation alone. However, the mechanisms by which D-lactylation influences mesangial cell activation and its potential effects on other renal resident cells, particularly podocytes and tubular epithelial cells, require further investigation. Nevertheless, our findings highlight a novel role for D-lactylation in IgAN pathogenesis. TRADITIONAL CHINESE MEDICINE MODULATES PTMS TO AMELIORATE IGAN Traditional Chinese medicine (TCM) offers a unique advantage in IgAN treatment by employing multicomponent and multitarget intervention strategies, supported by extensive clinical experience.[7] TCM, including both complex prescriptions and single compounds, exhibits particular promise in modulating PTMs for IgAN treatment. NF-κB pathway activation is a primary driver of podocyte injury in IgAN. Zhen Wu Tang, known for its yang-warming and diuretic effects, has demonstrated podocyte protection in IgAN rats by inhibiting NF-κB/NF-kappa-B inhibitor α (IκBα) phosphorylation.[8] Artesunate demonstrates promising therapeutic efficacy in IgAN. Mechanistically, it alleviates IgAN-associated fibrosis and oxidative stress by modulating Akt phosphorylation and promoting Nrf2 nuclear translocation.[9] Macrophages contribute to the inflammatory response in IgAN. Specifically, increased expression of extracellular matrix protein 1 within macrophages drives their polarization towards a proinflammatory phenotype, thereby mediating the production of inflammatory cytokines. Tripterygium wilfordii Hook. f., a TCM herb with a long history of use in treating various kidney diseases (including IgAN), contains the botanical triterpene celastrol as a key bioactive component. Celastrol inhibits proinflammatory macrophage activity in IgAN by directly promoting extracellular matrix protein 1 ubiquitination and subsequent proteasomal degradation.[10] It is worth emphasizing that whether these compounds directly target key enzymes involved in phosphorylation and ubiquitination in IgAN remains a completely unexplored yet highly valuable research direction. In this commentary, we clarify the critical roles of PTMs, particularly glycosylation and phosphorylation, in IgAN pathogenesis. While the upstream molecular mechanisms driving aberrant IgA1 glycosylation have been extensively characterized, the translational gap remains significant, with no clinically approved targeted therapies currently available to modulate this pathological process. TCM, with its rich repertoire of bioactive compounds, presents a promising yet underexplored resource for drug discovery in this context. A strategic focus on isolating and characterizing active constituents from empirically validated TCM formulations could yield novel therapeutic candidates for IgAN intervention. Beyond the well-documented glycosylation abnormalities, emerging evidence suggests potential involvement of other PTMs, including acetylation, ubiquitination, and small ubiquitin-like modifier modification (SUMOylation), in disease progression. However, these mechanisms remain poorly defined and warrant systematic investigation. Importantly, we are the first to propose investigating D-lactylation as a mechanistic direction for understanding IgAN pathogenesis. Furthermore, we have summarized that TCM includes both complex prescriptions and single compounds that target phosphorylation and ubiquitination pathways to ameliorate IgAN [Figure 1].Figure 1.: Novel molecular mechanisms of IgA nephropathy mediated by posttranslational modifications and traditional Chinese medicine therapeutic strategies. This figure was created with FigDraw. Akt, protein kinase B; ECM1, extracellular matrix protein 1; NF-κB, nuclear factor kappa B; IgA, immunoglobulin A; IgG, immunoglobulin G; Gd-IgA1, galactose-deficient IgA1; Ser, serine; Thr, threonine.Although the field of PTM research in IgAN is still in its nascent stages, the growing body of evidence strongly supports its potential to elucidate fundamental disease mechanisms, identify clinically relevant biomarkers, and pave the way for precision therapeutic strategies. This multifaceted approach may ultimately bridge the critical gap between mechanistic understanding and clinical translation in IgAN management. Financial support and sponsorship This work was supported by the National Natural Science Foundation of China (82374271), Guangdong Basic and Applied Basic Research Foundation (2023A1515012539) and the Fifth Batch of National Training Programs for Clinical Excellence in Traditional Chinese Medicine (National TCM Human Education Letter [2022] No.1). Author contributions Zeng Q: Conceptualization, Writing—Original draft preparation. Zhao SG: Writing—Reviewing and Editing. Wang M: Funding acquisition, Supervision, Project administration. All authors reviewed and approved the final version of the manuscript. Ethics approval and consent to participate Not applicable. Conflict of interest The authors declare no competing interests. Use of large language models, AI and machine learning tools None declared. Data availability statement No additional data.
Authors: Qin Zeng, Shangang Zhao, Ming Wang
Language: English
Subfield: Nephrology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
OpenAlex ID: W7128712541