Pulmonary fibrosis is an age-related, progressive, and fatal disease with a median survival of 3–5 years after diagnosis; idiopathic pulmonary fibrosis (IPF) is the most common type. It is characte...

Myo-inositol, a carbocyclic sugar, is believed to be relevant to renal pathobiology since the kidney is the major site for its catabolism. Its role in acute kidney injury (AKI) has not been fully investigated. Ferroptosis, a unique form of regulated cell death, is involved in various types of renal injuries. The relevance of myo-inositol with respect to the process of ferroptosis has not been explored either. Herein, our current exploratory studies revealed that supplementation of myo-inositol attenuates cisplatin-induced injury in cultured Boston University mouse proximal tubular (BUMPT) cells and renal tubules in vivo. Moreover, our studies unraveled that metabolic parameters pertaining to ferroptosis were disrupted in cisplatin-treated proximal tubular cells, which were seemingly remedied by the administration of myo-inositol. Mechanistically, we noted that cisplatin treatment led to the up-regulation of NOX4, a key enzyme relevant to ferroptosis, which was normalized by the administration of myo-inositol. Furthermore, we observed that changes in the NOX4 expression induced by cisplatin or myo-inositol were modulated by carboxy-terminus of Hsc70-interacting protein (CHIP), an E3 ubiquitin ligase. Taken together, our investigation suggests that myo-inositol promotes CHIP-mediated ubiquitination of NOX4 to decelerate the process of ferroptosis, leading to the amelioration of cisplatin-induced AKI.

Objective. This paper aims to explore novel ferroptosis‐related biomarkers for acute kidney injury (AKI). Methods. Various bioinformatic methods, such as differential expression analysis, functional annotation analysis, machine learning, and chemical‐gene network analysis, were used in this study. Furthermore, the expression and proferroptotic role of RPS7 were validated with further bioinformatics analysis and biochemical experiments. Results. GSE30718 dataset and GSE139061 dataset were used, and the differentially expressed genes (DEGs) were screened. The DEGs were overlapped with ferroptosis‐related genes and genes associated with AKI, which led to the identification of four candidate genes. Machine learning and ROC curve analysis were conducted, and RPS7 and TRIB3 were selected for diagnostic model analysis and functional analysis. Finally, the upregulation of RSP7 in cisplatin‐induced AKI was validated in cisplatin‐induced AKI, and its proferroptotic role was confirmed in cisplatin‐treated proximal tubular cells. Conclusion. Our results indicated that RPS7 might present as a novel ferroptosis‐related biomarker for AKI, and it derived ferroptosis to accentuate cisplatin‐induced AKI.

Carboxy-terminus of Hsc70-interacting protein (CHIP), an E3 ligase, modulates the stability of its targeted proteins to alleviate various pathological perturbations in various organ systems. Cisplatin is a widely used chemotherapeutic agent, but it is also known for its alarming renal toxicity. The role of CHIP in the pathogenesis of cisplatin-induced acute kidney injury (AKI) has not been adequately investigated. Herein, we demonstrated that CHIP was abundantly expressed in the renal proximal tubular epithelia, and its expression was downregulated in cisplatin-induced AKI. Further investigation revealed that CHIP overexpression or activation alleviated, while its gene disruption promoted, oxidative stress and apoptosis in renal proximal tubular epithelia induced by cisplatin. In terms of mechanism, CHIP interacted with and ubiquitinated NUR77 to promote its degradation, which consequently shielded BCL2 to maintain mitochondrial permeability of renal proximal tubular cells in the presence of cisplatin. Also, we demonstrated that CHIP interacted with NUR77 via its central coiled-coil (CC) domain, a non-canonical interactive pattern. In conclusion, these findings indicated that CHIP ubiquitinated and degraded its substrate NUR77 to attenuate intrinsic apoptosis in cisplatin-treated renal proximal tubular epithelia, thus providing a novel insight for the pathogenesis of cisplatin-induced AKI.