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Renal proximal tubular cells are highly vulnerable to different types of assaults during filtration and reabsorption, leading to acute renal dysfunction and eventual chronic kidney diseases (CKD). The chemotherapeutic drug cisplatin elicits cytotoxicity causing renal tubular cell death, but its executing mechanisms of action are versatile and elusive. Here, we show that cisplatin induces renal tubular cell apoptosis and ferroptosis by disrupting glutathione (GSH) metabolism. Upon cisplatin treatment, GSH metabolism is impaired leading to GSH depletion as well as the execution of mitochondria-mediated apoptosis and lipid oxidation-related ferroptosis through activating IL6/JAK/STAT3 signaling. Inhibition of JAK/STAT3 signaling reversed cell apoptosis and ferroptosis in response to cisplatin induction. Using a cisplatin-induced acute kidney injury (CAKI) mouse model, we found that inhibition of JAK/STAT3 significantly mitigates cisplatin nephrotoxicity with a reduced level of serum BUN and creatinine as well as proximal tubular distortion. In addition, the GSH booster baicalein also reclaims cisplatin-induced renal tubular cell apoptosis and ferroptosis as well as the in vivo nephrotoxicity. In conclusion, cisplatin disrupts glutathione metabolism, leading to renal tubular cell apoptosis and ferroptosis. Rewiring glutathione metabolism represents a promising strategy for combating cisplatin nephrotoxicity.

Ferroptosis is an iron-dependent programmed cell death associated with severe kidney diseases, linked to decreased glutathione peroxidase 4 (GPX4). However, the spatial distribution of renal GPX4-mediated ferroptosis and the molecular events causing GPX4 reduction during ischemia-reperfusion (I/R) remain largely unknown. Using spatial transcriptomics, we identify that GPX4 is situated at the interface of the inner cortex and outer medulla, a hyperactive ferroptosis site post-I/R injury. We further discover OTU deubiquitinase 5 (OTUD5) as a GPX4-binding protein that confers ferroptosis resistance by stabilizing GPX4. During I/R, ferroptosis is induced by mTORC1-mediated autophagy, causing OTUD5 degradation and subsequent GPX4 decay. Functionally, OTUD5 deletion intensifies renal tubular cell ferroptosis and exacerbates acute kidney injury, while AAV-mediated OTUD5 delivery mitigates ferroptosis and promotes renal function recovery from I/R injury. Overall, this study highlights a new autophagy-dependent ferroptosis module: hypoxia/ischemia-induced OTUD5 autophagy triggers GPX4 degradation, offering a potential therapeutic avenue for I/R-related kidney diseases.

Objective: The long non-coding RNA (lncRNA) colorectal neoplasia differentially expressed (CRNDE) is considered a carcinogenic promoter in various human malignancies. However, the role and underlying mechanism of action of CRNDE during carcinogenesis in neuroblastoma remain unknown., Methods: CRNDE transcript levels were detected in neuroblastoma tissues and adjacent normal tissues. The effects of CRNDE overexpression and knockdown on the viability of SH-SY5Y and SK-N-AS cells were determined using the Cell Counting Kit-8 (CCK-8) assay. Flow cytometry was performed to measure the role of CRNDE in apoptosis and the cell cycle in neuroblastoma cells. Moreover, the transwell assay was used to evaluate the role of CRNDE in the migration and invasion of tumor cells. The levels of ERK/MAPK pathway-related proteins were evaluated using western blotting. The in vivo role of CRNDE in tumor growth and apoptosis was evaluated in a xenograft mouse model of human neuroblastoma., Results: The relative expression of CRNDE was significantly higher in neuroblastoma tissues than in the adjacent normal tissues. Moreover, knockdown of CRNDE inhibited tumor cell proliferation and induced apoptosis and cell cycle arrest, whereas elevation of CRNDE promoted cell growth and inhibited apoptosis in neuroblastoma cells. In addition, depletion of CRNDE suppressed migration and invasion, whereas overexpression of CRNDE enhanced the migratory and invasive potential of SH-SY5Y and SK-N-AS cells. At the mechanistic level, western blotting showed that CRNDE exerted its oncogenic role by affecting the ERK/MAPK signaling pathway. Furthermore, animal experiments confirmed that CRNDE promotes tumor growth and inhibits apoptosis in neuroblastoma in vivo ., Conclusion: The present study revealed that CRNDE plays a critical role in the proliferation, apoptosis, migration, and invasion of neuroblastoma by altering the ERK/MAPK signaling pathway, representing a novel molecular target for the treatment of neuroblastoma., (Copyright © 2022 by the Association of Clinical Scientists, Inc.)