I read with great interest the recent study by Duan and colleagues (2026), who report that inhibition of G protein-coupled receptor kinase 2 (GRK2) mitigates cisplatin-induced acute and chronic nephrotoxicity through the regulation of the NOX4-mediated oxidative stress pathway. The authors propose a novel mechanism whereby GRK2 phosphorylates NOX4, suppresses its ubiquitination and thereby stabilises NOX4 to enhance the production of reactive oxygen species (ROS) in renal tubular epithelial cells (RTECs) (Duan et al., 2026). Furthermore, pharmacological inhibition of GRK2 with CP-25 is suggested to provide renoprotection without compromising the antitumour efficacy of cisplatin (Duan et al., 2026). These findings provide potentially valuable insights into the molecular mechanisms of cisplatin-induced kidney injury. Nevertheless, several mechanistic aspects of the proposed GRK2–NOX4 regulatory axis warrant further clarification. First, although the authors demonstrate that GRK2 promotes NOX4 phosphorylation, the specific phosphorylation sites involved remain unidentified (Duan et al., 2026). The kinase assays relied on a pan-phospho-serine/threonine antibody, which confirms phosphorylation but does not determine the precise residue targeted by GRK2. Identification of the phosphorylation site by mass spectrometry or site-directed mutagenesis would be essential to establish a direct regulatory mechanism. Previous studies have shown that NADPH oxidase activity is tightly regulated by multiple mechanisms, including protein–protein interactions and post-translational modifications such as phosphorylation, which often require precise mapping of phosphorylation residues to establish functional relevance (Brandes et al., 2014). Without this information, it remains uncertain whether GRK2 directly modifies NOX4 or whether the observed phosphorylation reflects secondary signalling events. Second, the mechanism linking GRK2-mediated phosphorylation to reduced NOX4 ubiquitination remains incompletely defined (Duan et al., 2026). NOX4 protein stability is known to be regulated by post-translational mechanisms, including ubiquitin-proteasome-dependent degradation (Tsubouchi et al., 2017). However, the current study does not identify the E3 ligase responsible for NOX4 ubiquitination, nor determines how GRK2-dependent phosphorylation interferes with this degradation pathway (Duan et al., 2026). Clarifying whether phosphorylation disrupts E3 ligase binding, alters NOX4 conformation or modifies subcellular localisation would significantly strengthen the proposed model. In the absence of such mechanistic evidence, the causal link between GRK2 activity and NOX4 stabilisation remains partly speculative. Third, the interpretation of epithelial–mesenchymal transition (EMT) in RTECs also deserves careful consideration. The study associates RTEC EMT with the generation of myofibroblasts and the progression of renal fibrosis in cisplatin-induced chronic kidney disease (Duan et al., 2026). However, increasing evidence suggests that RTECs rarely undergo complete EMT to become myofibroblasts in vivo (LeBleu et al., 2013). Instead, they typically exhibit a ‘partial EMT’ phenotype that contributes to maladaptive repair and fibrogenic signalling rather than direct fibroblast conversion (Humphreys et al., 2010). Therefore, interpreting EMT as a primary source of myofibroblasts may oversimplify the current understanding of renal fibrogenesis. A distinction between partial EMT and fibroblast transition would help refine the pathophysiological interpretation of these findings. Despite these considerations, the work by Duan et al. (2026) offers important insights into the role of oxidative stress signalling in cisplatin-induced nephrotoxicity and highlights GRK2 as a potentially attractive therapeutic target. Additional mechanistic clarification would further consolidate the proposed GRK2–NOX4 regulatory axis and may stimulate future studies aimed at refining therapeutic strategies for protecting renal function during cisplatin-based chemotherapy. Key protein targets and ligands in this article are hyperlinked to corresponding entries in https://www.guidetopharmacology.org and are permanently archived in the Concise Guide to PHARMACOLOGY 2025/26 (Alexander et al., 2025). Cheng Xue: Conceptualization; writing—original draft; writing—review and editing. None.
Cheng Xue (Thu,) studied this question.